阅读说明：本技术 包括用于治疗病症的可植入阻尼装置和治疗剂的组合疗法及相关系统和使用方法 (Combination therapy including an implantable damping device and a therapeutic agent for treating a condition and related systems and methods of use ) 是由 戴维·斯蒂芬·塞利尔马耶 安东尼·约翰·乌哈齐 佐兰·米利贾谢维奇 马克·卡内基 于 2019-11-26 设计创作，主要内容包括：本文公开了使用可植入阻尼装置和治疗剂(例如,药物)组合治疗病症的装置,系统,和方法。用于治疗一种或多种病症(如神经学病症)的影响的方法包括提供治疗患者的病症的可植入阻尼装置和至少一种其他疗法(如治疗剂)。可植入阻尼装置包括挠性阻尼构件和缓和物质并且可以与血管并置放置。挠性阻尼构件形成具有内表面和外表面的大体上管状结构,内表面由具有部分可变形部分的侧壁形成。缓和物质设置在部分可变形部分内并且响应于搏动血流在部分可变形部分内纵向和/或径向移动。(Disclosed herein are devices, systems, and methods for treating a condition using an implantable damping device in combination with a therapeutic agent (e.g., a drug). A method for treating the effects of one or more conditions (e.g., neurological conditions) includes providing an implantable damping device and at least one other therapy (e.g., therapeutic agent) for treating a condition in a patient. The implantable damping device includes a flexible damping member and a dampening substance and may be placed in apposition to the blood vessel. The flexible damping member forms a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having a partially deformable portion. A mitigating substance is disposed within the partially deformable portion and moves longitudinally and/or radially within the partially deformable portion in response to pulsatile blood flow.)

1. A device for treating dementia, comprising:

a flexible, compliant damping member configured to intravascularly position within an artery at a treatment site, the damping member being transformable between a low-profile state for delivery to the treatment site and a post-dilation state, wherein the damping member comprises a generally tubular sidewall having (a) an outer surface, (b) an inner surface defining a lumen configured to direct blood flow, (c) a first end, (d) a second end opposite the first end along a length of the damping member, and (e) a damping region between the first and second ends, wherein the inner and outer surfaces are spaced apart a distance greater at the damping region than at either of the first or second ends;

wherein the damping member absorbs a portion of the pulsatile energy of the blood as the blood flows through the damping member during systole, thereby reducing the magnitude of the pulse pressure transmitted to a portion of the blood vessel distal to the damping device.

2. A device for treating an artery selected from the group consisting of the left common carotid artery, the right common carotid artery, the brachiocephalic artery, the ascending aorta, the internal carotid artery, or the abdominal aorta, the device comprising:

a covering made of an elastically deformable material, and

a co-moulding adapted to secure two opposing edges of the wrap around the artery,

wherein the elastically deformable material is configured to radially expand in a systolic phase and radially contract in a diastolic phase.

3. The device of claim 2, wherein the mating formation comprises a suture and/or a staple.

4. The apparatus of claim 2, wherein the mating formation comprises a zip lock.

5. A device for treating or mitigating the effects of dementia, comprising:

a damping member having a low-profile state and a deployed state, wherein in the deployed state the damping member comprises a deformable, generally tubular sidewall having an outer surface and an inner surface, the inner surface undulating in a longitudinal direction, and wherein the sidewall is configured to be positioned in apposition to a vessel wall to absorb pulsatile energy transmitted by blood flowing through the vessel.

6. The device of claim 5, wherein the damping member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.

7. The apparatus of claim 5 or claim 6, wherein the damping member is configured to position it in apposition with the ascending aorta.

8. The device according to any of claims 5-7, wherein the damping member is configured to be positioned in apposition with an inner surface of a vessel wall.

9. The device according to any of claims 5-8, wherein the damping member is configured to be positioned in apposition with an outer surface of a vessel wall.

10. The device of any one of claims 5-9, wherein the sidewall has an inner diameter, and the inner diameter increases and decreases in an axial direction when the damping member is in the deployed state.

11. The device of any one of claims 5-10, wherein the cross-sectional area decreases and increases in the longitudinal direction.

12. The device according to any of claims 5-11, wherein the damping member does not constrain the diameter of the vessel wall when the damping member is positioned adjacent to the vessel wall.

13. A device for treating or mitigating the effects of dementia, comprising:

an elastic member having a low-profile state and a deployed state for delivery to a treatment site at a vessel wall, wherein in the deployed state, the elastic member is configured to be adjacent to an arterial wall and form a generally tubular structure having an inner diameter, an outer surface, and an undulating inner surface, and wherein at least one of the outer diameter and the inner diameter increases and decreases in response to increases and decreases, respectively, of an intravascular pulse pressure.

14. The apparatus of claim 13, wherein the elastic member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.

15. The apparatus according to claim 13 or claim 14, wherein the resilient member is configured to position it in apposition with the ascending aorta.

16. The device according to any of claims 13-15, wherein the elastic member is configured to be positioned in apposition with an inner surface of the vessel wall.

17. The device of any one of claims 13-16, wherein the resilient member is configured to be positioned in apposition with an outer surface of the vessel wall.

18. The device of any one of claims 13-17, wherein the sidewall has an inner diameter, and the inner diameter increases and decreases in an axial direction when the resilient member is in the deployed state.

19. The device of any one of claims 13-18, wherein the cross-sectional area decreases and increases in the longitudinal direction.

20. The device of any one of claims 13-19, wherein the elastic member does not constrain the diameter of a vessel wall when the elastic member is positioned adjacent to the vessel wall.

21. A device for treating or mitigating the effects of dementia, comprising:

a damping member comprising a mitigating substance, the damping member having a low-profile configuration and a deployed configuration, wherein, when the damping member is in the deployed configuration, the damping member forms a substantially tubular structure configured to be positioned along a perimeter of an artery such that, when a pulse wave traveling through the artery applies a stress at a first axial location along a length of the tubular structure, at least a portion of the mitigating substance moves along the length of the tubular structure away from the first location to a second axial location.

22. The apparatus of claim 21, further comprising a structural element coupled to the damping member.

23. The device of claim 21 or claim 22, wherein in a deployed state, the damping member is configured to wrap around at least a portion of a perimeter of the artery.

24. The device of any one of claims 21-23, wherein in the deployed state, the device has a preset helical configuration.

25. The device of any one of claims 21-24, wherein the damping member comprises a liquid.

26. The device of any one of claims 21-25, wherein the damping member comprises a gas.

27. The device of any one of claims 21-26, wherein the damping member comprises a gel.

28. The device of any one of claims 21-27, wherein in the deployed configuration, the damping member is configured to position it in apposition with an outer surface of the artery wall.

29. The device of any one of claims 21-28, wherein in a deployed configuration, the damping member is configured to position it around an artery wall such that an inner surface of the damping member is in contact with blood flowing through the artery.

30. A device for treating or mitigating the effects of dementia, comprising:

a damping member comprising a plurality of fluid particles, the damping member having a low-profile configuration and an expanded configuration, wherein, when the damping member is in the expanded configuration, the damping member is configured to position its location along a perimeter of the artery at a treatment site along a length of the artery,

wherein, when the damping member is in a deployed configuration and its position is disposed at the treatment site, a wavefront traveling through the length of the artery redistributes at least a portion of the fluid particles along the length of the damping member such that the inner diameter of the damping member increases at the axial location along the damping member aligned with the wavefront and the inner diameter of the damping member decreases at another axial location along the damping member.

31. The apparatus of claim 30, further comprising a structural element coupled to the damping member.

32. The device of claim 30 or claim 31, wherein in a deployed state, the damping member is configured to wrap around at least a portion of a perimeter of the artery.

33. The device of any one of claims 30-32, wherein in the deployed state, the device has a preset helical configuration.

34. The device of any one of claims 30-33, wherein the damping member comprises a liquid.

35. The device of any one of claims 30-34, wherein the damping member comprises a gas.

36. The device of any one of claims 30-35, wherein the damping member comprises a gel.

37. The device of any one of claims 30-36, wherein in the deployed configuration, the damping member is configured to position it in apposition with an outer surface of the artery wall.

38. The device of any one of claims 30-37, wherein in a deployed configuration, the damping member is configured to position it around an artery wall such that an inner surface of the damping member is in contact with blood flowing through the artery.

39. A method for treating or mitigating the effects of dementia, comprising:

positioning a damping device in apposition with at least one of the brachiocephalic artery, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch, the damping device comprising a resilient, generally tubular sidewall, wherein the damping device absorbs pulsatile energy delivered by blood flowing through at least one of the brachiocephalic artery, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch.

40. A method for treating or mitigating the effects of dementia, comprising:

positioning a damping device in apposition with a wall of an artery that delivers blood to the brain, the damping device comprising a resilient, generally tubular sidewall having an outer surface and an undulating inner surface; and

a profile of at least one of the inner surface and the outer surface changes in response to a pulse pressure wave in blood flowing through the blood vessel.

41. A method for treating at least one of a brachiocephalic artery, a right common carotid artery, a left common carotid artery, an ascending aorta, and an aortic arch, the method comprising:

positioning a damping device in apposition with a vessel wall, the damping device comprising a resilient, generally tubular sidewall;

expanding at least one of the inner diameter and the outer diameter of the damping device in response to an increase in pulse pressure; and

contracting at least one of the inner diameter and the outer diameter of the damping device in response to a decrease in pulse pressure.

42. A method of treating a blood vessel selected from the group consisting of the left common carotid artery, the right common carotid artery, or the brachiocephalic artery, the carotid artery, any of the foregoing branches, and the ascending aorta, the method comprising:

wrapping an elastically deformable material around the artery; and

attaching a first edge of the elastically deformable material to an opposing second edge of the elastically deformable material such that an inner diameter of the elastically deformable material is smaller than an initial outer diameter of the artery during a systolic phase.

43. A method for treating or mitigating the effects of dementia, comprising:

positioning a damping member along a length of an artery, the damping member comprising a mitigating material; and

in response to a pulse wave traveling through the blood in the artery, redistributing at least a portion of the mitigating compound along a length of the damping member, thereby attenuating at least a portion of energy of the pulse wave in the blood.

44. A method for treating or mitigating the effects of dementia, comprising:

positioning a damping member along a length of an artery, the damping member comprising a plurality of fluid particles; and

moving a portion of the fluid particles away from an axial position along the damping member aligned with a wave front of a pulse wave, thereby increasing the inner diameter of the damping member.

45. A device for treating an artery selected from the group consisting of the left common carotid artery, the right common carotid artery, the brachiocephalic artery, the ascending aorta, the internal carotid artery, or the abdominal aorta, the device comprising:

a covering made of an elastically deformable material, and

a co-moulding adapted to secure two opposing edges of the wrap around the artery,

wherein the elastically deformable material is configured to radially expand in a systolic phase and radially contract in a diastolic phase.

46. The device of claim 45, wherein the wrap completely or substantially completely encircles the artery over a portion of its length when in place around the artery.

47. The device of claim 45 or 46, the co-operating formations comprising sutures and/or staples.

48. The apparatus of any one of claims 45-47, wherein the mating formation comprises a zip lock.

49. A device for treating or mitigating the effects of dementia, comprising:

a damping member comprising a deformable, generally tubular sidewall having an outer surface and an inner surface, the inner surface undulating in a longitudinal direction, and wherein the sidewall is configured to be positioned in apposition to a vessel wall to absorb pulsatile energy transmitted by blood flowing through the vessel.

50. The device of claim 49 wherein the damping member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.

51. The apparatus according to claim 49 or claim 50, wherein the damping member is configured to position it in apposition with the ascending aorta.

52. The device of any one of claims 49-51, wherein the damping member is configured to be positioned in apposition with an inner surface of a vessel wall.

53. The device of any one of claims 49-52, wherein the damping member is configured to be positioned in apposition with an outer surface of a vessel wall.

54. The device of any one of claims 49-53, wherein the sidewall has an inner diameter, and the inner diameter increases and decreases in an axial direction when the damping member is in a deployed state.

55. The device of any one of claims 49-54, wherein the cross-sectional area decreases and increases in the longitudinal direction.

56. The device of any one of claims 49-55, wherein the outer surface has a substantially cylindrical shape.

57. The device of any one of claims 49-56, wherein the outer surface has an undulating shape.

58. The device of any one of claims 49-57, wherein the damping member does not constrain the diameter of the vessel wall when the damping member is positioned adjacent to the vessel wall.

59. A device for treating or mitigating the effects of dementia, comprising:

an elastic member configured to be adjacent to an artery wall and form a generally tubular structure having an inner diameter, an outer surface, and an undulating inner surface, and wherein at least one of the outer diameter and the inner diameter increases and decreases in response to increases and decreases, respectively, in intravascular pulse pressure.

60. The device of claim 59, wherein the elastic member is configured to be positioned in apposition with at least one of a left common carotid artery, a right common carotid artery, and a brachiocephalic artery.

61. The apparatus according to claim 59 or claim 60, wherein the resilient member is configured to position it in apposition with the ascending aorta.

62. The device of any one of claims 59-61, wherein the resilient member is configured to be positioned in apposition with an inner surface of the vessel wall.

63. The device of any one of claims 59-62, wherein the resilient member is configured to be positioned in apposition with an outer surface of the vessel wall.

64. The device of any one of claims 59-63, wherein the sidewall has an inner diameter, and the inner diameter increases and decreases in an axial direction when the resilient member is in the deployed state.

65. The device of any one of claims 59-64, wherein the cross-sectional area decreases and increases in the longitudinal direction.

66. The device of any one of claims 59-65, wherein the elastic member does not constrain the diameter of a vessel wall when the elastic member is positioned adjacent to the vessel wall.

67. The device of any one of claims 59-66, wherein the damping or elastic member has a low-profile state and a deployed state.

68. The device of claim 67, wherein the deployed state is for delivery to a treatment site at a vessel wall.

69. The device of claim 67 or 68, wherein the damping or resilient member has a first, smaller diameter when in the low-profile state and a second, larger diameter when in the deployed state.

70. A device for treating or mitigating the effects of dementia, comprising:

a damping member comprising a mitigating material, wherein the damping member forms a generally tubular structure having an axis, wherein the mitigating material is axially movable relative to the tubular structure, and wherein the damping member is configured to position it along a perimeter of an artery such that when a pulse wave traveling through the artery applies stress at a first axial position along a length of the tubular structure, at least a portion of the mitigating material moves along the length of the tubular structure away from the first position to a second axial position.

71. The device of claim 70, wherein the soothing substance comprises a quantity of fluid and/or gel comprising particles contained within a flexible member, and the particles are axially movable within the flexible member relative to the tubular structure.

72. The apparatus of claim 70 or claim 71, wherein the flexible member is radially deformable relative to the tubular structure at least some locations along the length of the tubular structure.

73. The device of any one of claims 70-72, further comprising a structural element coupled to the damping member.

74. The device of any one of claims 70-73, wherein, in a deployed state, the damping member is configured to wrap around at least a portion of a perimeter of the artery.

75. The device of claim 74 in which the damping member includes interruptions along its length to fit around portions of the circumference of the artery.

76. The device of claim 75, further comprising cooperating sealing arrangements located on or near opposing edges of the discontinuity to connect the edges together once the damping member has been fitted around a portion of the circumference of the artery.

77. The device of any one of claims 70-76, wherein in the deployed state, the device has a preset helical configuration.

78. The device of any one of claims 70-77, wherein the damping member comprises a liquid.

79. The device of any one of claims 70-78 wherein the damping member comprises a gas.

80. The device of any one of claims 70-79, wherein the damping member comprises a gel.

81. The device of any one of claims 70-80, wherein in a deployed configuration, the damping member is configured to position it in apposition with an outer surface of an arterial wall.

82. The device of any one of claims 70-81, wherein in a deployed configuration, the damping member is configured to position it around an artery wall such that an inner surface of the damping member is in contact with blood flowing through the artery.

83. A device for treating or mitigating the effects of dementia, comprising:

wherein the fluid particles are axially movable along at least a portion of the length of a damping structure, the damping member being configured to position its location along the circumference of an artery at a treatment site along the length of the artery,

wherein, when the damping member is in a deployed configuration and its position is disposed at the treatment site, a wavefront traveling through the length of the artery redistributes at least a portion of the fluid particles along the length of the damping member such that the inner diameter of the damping member increases at the axial location along the damping member aligned with the wavefront and the inner diameter of the damping member decreases at another axial location along the damping member.

84. The device of claim 83 wherein the fluid particles are contained within a flexible member and the particles are movable within the flexible member along a length of the damping member.

85. The device of claim 84 wherein the flexible member is radially deformable relative to the damping member at least some locations along the length of the damping member.

86. The device of any one of claims 83-85, further comprising a structural element coupled to the damping member.

87. The device of any one of claims 83-86 wherein, in a deployed state, the damping member is configured to wrap around at least a portion of a perimeter of the artery.

88. The device of claim 87 in which the damping member includes interruptions along its length to fit around portions of the circumference of the artery.

89. The device of claim 88, further comprising cooperating sealing arrangements located on or near opposing edges of the discontinuity to connect the edges together once the damping member has been fitted around a portion of the circumference of the artery.

90. The device of any one of claims 83-89, wherein in the deployed state, the device has a preset helical configuration.

91. The device of any one of claims 83-90 wherein the damping member comprises a liquid.

92. The device of any one of claims 83-91 wherein the damping member comprises a gas.

93. The device of any one of claims 83-92 wherein the damping member comprises a gel.

94. The device of any one of claims 83-93, wherein in the deployed configuration, the damping member is configured to position it in apposition with an outer surface of the arterial wall.

95. The device of any one of claims 83-94, where in a deployed configuration, the damping member is configured to position it around an artery wall such that an inner surface of the damping member is in contact with blood flowing through the artery.

96. The device of any one of claims 83-95 wherein the damping member has a low-profile configuration and a deployed configuration.

97. A method for treating or alleviating the effects of one or more disorders in a subject in need thereof, the method comprising:

there is provided a device for treating or alleviating the effects of one or more conditions,

and configured for placement in apposition to a blood vessel, the device

Including

Forming a flexible damping member of a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having one or more at least partially deformable portions, and

a mitigating substance disposed within one or more at least partially deformable portions of the sidewall, configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel; and

at least one additional therapy is provided for treating or mitigating the effects of one or more conditions in combination with the device.

98. The method of claim 97, wherein the at least one other therapy is selected from the group consisting of a β -site amyloid precursor protein cleaving enzyme (BACE) inhibitor, a tau inhibitor, an amyloid immunotherapeutic agent, an amyloid aggregation inhibitor, an anti-inflammatory agent, a neuroprotective agent, an antiviral agent, a metabolic agent, a thiazolidinedione agent, a neurotransmitter agent, a mitochondrial dynamics modulator, a membrane contact site modifier, a lysosomal function enhancer, an endosomal function enhancer, a transport enhancer, a protein folding modifier, a protein aggregation modifier, a protein stability modifier, and a protein processing modifier.

99. The method of claim 98, wherein the amyloid immunotherapeutic agent is an anti-amyloid antibody.

100. The method of claim 99, wherein the anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb 158.

101. The method of claim 100, wherein the humanized version of mouse monoclonal antibody mAb158 is an IgG1 antibody.

102. The method of claim 101, wherein the humanized version of the mouse monoclonal antibody mAb158 IgG1 antibody is BAN 2401.

103. The method of claim 99, wherein said anti-amyloid antibody is a human anti-amyloid antibody.

104. The method of claim 103, wherein the human anti-amyloid antibody is aducartuzumab.

105. The method of any one of claims 97-104, wherein the at least one other therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid beta protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

106. The method of any one of claims 97-105, wherein the other therapy is provided at a first dose that is lower than a second dose provided without the device.

107. The method of any one of claims 97-106, wherein the additional therapy is provided at a first dosing regimen that is less than a second dosing regimen provided without the device.

108. The method of any one of claims 97-107, wherein the other therapy is provided via a first pathway different from a second pathway provided without the device.

109. The method of any one of claims 97 to 108, wherein the additional therapy is provided by administering the additional therapy to a subject in need thereof.

110. The method of claim 109, wherein the additional therapy is administered to the subject in need thereof by eluting the additional therapy from at least a portion of the device.

111. The method of any one of claims 97-110, wherein the condition is neurodegeneration.

112. The method of claim 111, wherein neurodegeneration further comprises alzheimer's disease, dementia, and/or cognitive disorders.

113. The method of any one of claims 97-112, wherein the device has a low-profile state and a deployed state, and the sidewall is substantially tubular when in the deployed state.

114. The method of any one of claims 97-113, wherein the soothing substance is configured to expand in response to an increase in the intravascular blood pressure and relax with a subsequent decrease in the intravascular blood pressure.

115. The method according to claim 114, wherein the flexible damping member applies a stress at the first location along the length of the tubular structure when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel.

116. The method of claim 115, wherein at least a portion of the mitigating substance moves longitudinally and/or radially along the length of the tubular structure after the stress is applied at the first location.

117. The method of claim 116, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion of the flexible damping member to a second location within the first deformable portion.

118. The method of claim 117, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is further configured to move longitudinally and/or radially within a second deformable portion of the flexible damping member from the first location to a third location.

119. The method of any one of claims 97 to 118, wherein the inner and/or outer surface has a substantially cylindrical shape or an undulating shape that undulates in a longitudinal direction.

120. The method of any of claims 97-119, wherein the flexible damping member is further configured to position around at least a portion of a perimeter of the vessel wall, and a pulse wave traveling through the vessel applies stress to a first region of the damping member, at least a portion of the mitigating material moving a second region away from the first region of the damping member, such that the damping member absorbs at least a portion of energy of the pulse wave, thereby reducing the stress on the vessel wall distal to the device.

121. The method of any one of claims 97-120, wherein the device is further configured to deploy within a lumen of the blood vessel such that an outer surface of an anchoring member is juxtaposed with a lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the blood vessel lumen.

122. The method of claim 121, wherein when the device is deployed within the lumen of the vessel and a pulse wave traveling through the vessel applies stress to the damping member at the third location, at least a portion of the mitigating material moves away from the damping member at the third location to a fourth location such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal of the device.

123. A method for treating or alleviating the effects of one or more disorders in a subject in need thereof, the method comprising:

there is provided a device for treating or alleviating the effects of one or more conditions,

and configured for placement in apposition to a blood vessel, the device

Including

Forming a flexible damping member of a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having one or more at least partially deformable portions, and

a mitigating substance disposed within one or more at least partially deformable portions of the sidewall, configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel; and

wherein at least one other therapy to treat or mitigate the effects of one or more conditions has been previously provided to a subject in need thereof.

124. The method of claim 123, wherein the at least one other therapy is selected from the group consisting of a β -site amyloid precursor protein cleaving enzyme (BACE) inhibitor, a tau inhibitor, an amyloid immunotherapeutic agent, an amyloid aggregation inhibitor, an anti-inflammatory agent, a neuroprotective agent, an antiviral agent, a metabolic agent, a thiazolidinedione agent, a neurotransmitter agent, a mitochondrial dynamics modulator, a membrane contact site modifier, a lysosomal function enhancer, an endosomal function enhancer, a transport enhancer, a protein folding modifier, a protein aggregation modifier, a protein stability modifier, and a protein processing modifier.

125. The method of claim 124, wherein said amyloid immunotherapeutic agent is an anti-amyloid antibody.

126. The method of claim 125, wherein the anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb 158.

127. The method of claim 126, wherein the humanized version of mouse monoclonal antibody mAb158 is an IgG1 antibody.

128. The method of claim 127, wherein the IgG1 antibody is BAN 2401.

129. The method of claim 125, wherein said anti-amyloid antibody is a human anti-amyloid antibody.

130. The method of claim 129, wherein the human anti-amyloid antibody is aducartuzumab.

131. The method of any one of claims 123-130, wherein the at least one other therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid β protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

132. The method of any one of claims 123-131 wherein the other therapy is provided at a first dose that is lower than a second dose provided without the device.

133. The method of any one of claims 123-132 wherein the other therapy is provided at a first dosage regimen that is less than a second dosage regimen provided without the device.

134. The method of any one of claims 123-133 wherein the other therapy is provided via a first pathway different from a second pathway provided without the device.

135. The method of any one of claims 123-134, wherein the additional therapy is provided by administering the additional therapy to a subject in need thereof.

136. The method of claim 135, wherein the additional therapy is administered to the subject in need thereof by eluting the additional therapy from at least a portion of the device.

137. The method of any one of claims 123-136, wherein the disorder is neurodegeneration.

138. The method of claim 137, wherein neurodegeneration further comprises alzheimer's disease, dementia, and/or cognitive disorders.

139. The method of any one of claims 123-138 wherein the device has a low profile state and a deployed state, and the sidewall is substantially tubular when in the deployed state.

140. The method of any one of claims 123-139, wherein the modifying substance is configured to expand in response to an increase in the intravascular blood pressure and relax with a subsequent decrease in the intravascular blood pressure.

141. The method of claim 140 wherein the flexible damping member applies stress at the first location along the length of the tubular structure when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel.

142. The method of claim 141, wherein at least a portion of the mitigating substance moves longitudinally and/or radially along the length of the tubular structure after the stressing at the first location.

143. The method of claim 142, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion of the flexible damping member to a second location within the first deformable portion.

144. The method of claim 143, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is further configured to move longitudinally and/or radially within a second deformable portion of the flexible damping member from the first location to a third location.

145. The method as claimed in any one of claims 123-144, wherein the inner and/or outer surface has a substantially cylindrical shape or an undulating shape undulating in the longitudinal direction.

146. The method of any one of claims 123-145, wherein the flexible damping member is further configured to position around at least a portion of a perimeter of the vessel wall, and a pulse wave traveling through the vessel applies stress to a first region of the damping member, at least a portion of the mitigating material moving away from the first region to a second region of the damping member, such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal to the device.

147. The method of any one of claims 123-146, wherein the device is further configured to be deployed within the lumen of the blood vessel such that an outer surface of an anchoring member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the lumen of the blood vessel.

148. The method of claim 147, wherein when the device is deployed within the lumen of the blood vessel and a pulse wave traveling through the blood vessel applies stress on the damping member at a third location, at least a portion of the mitigating substance moves away from the damping member at the third location to a fourth location such that the damping member absorbs at least a portion of energy of the pulse wave, thereby reducing the stress on the vessel wall distal of the device.

149. A method for treating or alleviating the effects of one or more disorders in a subject in need thereof, the method comprising:

providing to a subject in need thereof at least one therapy for treating or attenuating the effects of one or more conditions, wherein a device for treating or attenuating the effects of one or more conditions has been previously provided to the subject and is placed in juxtaposition within a blood vessel, said device comprising

Forming a flexible damping member of a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having one or more at least partially deformable portions, and

a mitigating substance disposed within one or more at least partially deformable portions of the sidewall is configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel.

150. The method of claim 149, wherein the at least one other therapy is selected from the group consisting of a β -site amyloid precursor protein cleaving enzyme (BACE) inhibitor, a tau inhibitor, an amyloid immunotherapeutic agent, an amyloid aggregation inhibitor, an anti-inflammatory agent, a neuroprotective agent, an antiviral agent, a metabolic agent, a thiazolidinedione agent, a neurotransmitter agent, a mitochondrial dynamics modulator, a membrane contact site modifier, a lysosomal function enhancer, an endosomal function enhancer, a transport enhancer, a protein folding modifier, a protein aggregation modifier, a protein stability modifier, and a protein processing modifier.

151. The method of claim 150, wherein said amyloid immunotherapeutic agent is an anti-amyloid antibody.

152. The method of claim 151, wherein the anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb 158.

153. The method of claim 152, wherein the humanized version of mouse monoclonal antibody mAb158 is an IgG1 antibody.

154. The method of claim 153, wherein the IgG1 antibody is BAN 2401.

155. The method of claim 151, wherein the anti-amyloid antibody is a human anti-amyloid antibody.

156. The method of claim 155, wherein the human anti-amyloid antibody is aducartuzumab.

157. The method of any one of claims 149-156, wherein the at least one other therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid β protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

158. The method of any one of claims 149-157, wherein the other therapy is provided at a first dose that is lower than a second dose provided without the device.

159. The method of any one of claims 149-158, wherein the additional therapy is provided at a first dosage regimen that is less than a second dosage regimen provided without the device.

160. The method of any one of claims 149-159, wherein the additional therapy is provided via a first pathway different from a second pathway provided without the device.

161. The method of any one of claims 149-160, wherein the additional therapy is provided by administering the additional therapy to a subject in need thereof.

162. The method of claim 161, wherein the additional therapy is administered to the subject in need thereof by eluting the additional therapy from at least a portion of the device.

163. The method of any one of claims 149-162, wherein the disorder is neurodegeneration.

164. The method of claim 163, wherein neurodegeneration further comprises alzheimer's disease, dementia, and/or cognitive disorders.

165. The method of any one of claims 149-164, wherein the device has a low-profile state and a deployed state, and the sidewall is substantially tubular when in the deployed state.

166. The method of any one of claims 149-165, wherein the modifying substance is configured to expand in response to an increase in the intravascular blood pressure and relax with a subsequent decrease in the intravascular blood pressure.

167. The method of claim 166, wherein the flexible damping member applies stress at the first location along the length of the tubular structure when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel.

168. The method of claim 167, wherein at least a portion of the mitigating substance moves longitudinally and/or radially along the length of the tubular structure after the stressing at the first location.

169. The method of claim 168 wherein, upon application of the stress at the first location, at least a portion of the mitigating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion of the flexible damping member to a second location within the first deformable portion.

170. The method of claim 169, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is further configured to move longitudinally and/or radially within a second deformable portion of the flexible damping member from the first location to a third location.

171. The method as claimed in any one of claims 149-170, wherein the inner and/or outer surface has a substantially cylindrical shape or an undulating shape undulating in a longitudinal direction.

172. The method of any one of claims 149-171, wherein the flexible damping member is further configured to position around at least a portion of the perimeter of the vessel wall, and a pulse wave traveling through the vessel applies stress to a first region of the damping member, at least a portion of the mitigating material moving away from the first region to a second region of the damping member, such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal to the device.

173. The method of any one of claims 149-172, wherein the device is further configured to deploy within the lumen of the blood vessel such that an outer surface of an anchoring member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the lumen of the blood vessel.

174. The method of claim 173, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress on the damping member at the third location, at least a portion of the mitigating substance moves away from the damping member at the third location to a fourth location such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal of the device.

175. A system for treating or mitigating the effects of one or more conditions in a subject in need thereof, the system comprising:

at least one therapeutically effective amount for treating or alleviating the effects of one or more conditions,

a device for treating or alleviating the effects of one or more conditions,

the device comprises

Forming a flexible damping member of a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having one or more at least partially deformable portions, and

a mitigating substance disposed within one or more at least partially deformable portions of the sidewall is configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel.

176. The system of claim 175, wherein the at least one other therapy is selected from a beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, a tau inhibitor, an amyloid immunotherapeutic agent, an amyloid aggregation inhibitor, an anti-inflammatory agent, a neuroprotective agent, an antiviral agent, a metabolic agent, a thiazolidinedione agent, a neurotransmitter agent, a mitochondrial dynamics modulator, a membrane contact site modifier, a lysosomal function enhancer, an endosomal function enhancer, a transport enhancer, a protein folding modifier, a protein aggregation modifier, a protein stability modifier, and a protein processing modifier.

177. The system of claim 176, wherein the amyloid immunotherapeutic agent is an anti-amyloid antibody.

178. The system of claim 177, wherein the anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb 158.

179. The system of claim 178, wherein the humanized version of mouse monoclonal antibody mAb158 is an IgG1 antibody.

180. The system of claim 179, wherein the IgG1 antibody is BAN 2401.

181. The system of claim 177, wherein the anti-amyloid antibody is a human anti-amyloid antibody.

182. The system of claim 181, wherein the human anti-amyloid antibody is aducartuzumab.

183. The system of any one of claims 175-182, wherein the at least one other therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid β protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

184. The system of any one of claims 175-183, wherein the other therapy is provided at a first dose that is lower than a second dose provided without the device.

185. The system of any one of claims 175-184 wherein the other therapy is provided at a first dosage regimen that is less than a second dosage regimen provided without the device.

186. The system of any one of claims 175-185, wherein the other therapy is provided via a first pathway different from a second pathway provided without the device.

187. The system of any one of claims 175-186, wherein the other therapy is provided by administering the other therapy to a subject in need thereof.

188. The system of claim 187, wherein the additional therapy is administered to the subject in need thereof by eluting the additional therapy from at least a portion of the device.

189. The system of any one of claims 175-188, wherein the disorder is neurodegeneration.

190. The system of claim 189, wherein neurodegeneration further comprises alzheimer's disease, dementia, and/or cognitive disorders.

191. The system of any one of claims 175-190, wherein the inner and/or outer surface has a generally cylindrical shape or an undulating shape undulating in a longitudinal direction.

192. The system of any one of claims 175-191 wherein the device has a low profile and a deployed state and the sidewall is substantially tubular when in the deployed state.

193. The system of any one of claims 175-192, wherein the mitigating substance is configured to expand in response to an increase in the intravascular blood pressure and relax with a subsequent decrease in the intravascular blood pressure.

194. The system of claim 193 wherein the flexible damping member applies stress at the first location along the length of the tubular structure when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel.

195. The system of claim 194, wherein at least a portion of the mitigating substance moves longitudinally and/or radially along the length of the tubular structure after the stress is applied at the first location.

196. The system of claim 195 wherein, upon application of the stress at the first location, at least a portion of the mitigating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion of the flexible damping member to a second location within the first deformable portion.

197. The system of claim 196, wherein upon application of the stress at the first location, at least a portion of the mitigating substance is further configured to move longitudinally and/or radially within a second deformable portion of the flexible damping member from the first location to a third location.

198. The system of any one of claims 175-197 wherein the flexible damping member is further configured to position around at least a portion of a perimeter of the vessel wall and a pulse wave traveling through the vessel applies stress to a first region of the damping member and at least a portion of the mitigating material moves away from the first region to a second region of the damping member such that the damping member absorbs at least a portion of the energy of the pulse wave thereby reducing the stress on the vessel wall distal of the device.

199. The system of any one of claims 175-198 wherein the device is further configured to deploy within the lumen of the blood vessel such that an outer surface of the anchoring member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the lumen of the blood vessel.

200. The system of claim 199, wherein when the device is deployed within the lumen of the vessel and a pulse wave traveling through the vessel applies stress on the damping member at the third location, at least a portion of the mitigating substance moves away from the damping member at the third location to a fourth location such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal of the device.

201. A system for treating or mitigating the effects of one or more conditions in a subject in need thereof, the system comprising:

at least one therapeutically effective amount for treating or alleviating the effects of one or more conditions,

a device for treating or alleviating the effects of one or more conditions,

the device comprises

A flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed by a sidewall having one or more at least partially deformable portions configured to move longitudinally and/or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel, and

a mitigating substance disposed within one or more at least partially deformable portions of the sidewall, configured to move longitudinally and/or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel;

wherein an effective amount of at least one therapy for treating or alleviating the effects of one or more conditions is carried by at least one or more of the at least partially deformable portions of the device, and

wherein an effective amount of at least one therapy for treating or alleviating the effects of one or more conditions is released from the device when the one or more at least partially deformable portions are at least partially deformed.

202. The system of claim 201, wherein the effective amount of the at least one therapy further comprises a first effective amount of the at least one therapy and a second effective amount of the at least one therapy.

203. The system of claim 202, wherein the second effective amount of the at least one therapy is greater than the first effective amount of the at least one therapy.

204. The system of claim 203 wherein the one or more at least partially deformable portions are at least partially deformed to a first degree of deformation in response to a first pulsatile blood flow within the blood vessel.

205. The system of claim 204, wherein the one or more at least partially deformable portions are at least partially deformed to a second degree of deformation in response to second pulsatile blood flow in the blood vessel.

206. The system of claim 205, wherein the second degree of deformation is greater than the first degree of deformation.

207. The system of claim 206, wherein the first effective amount of the at least one therapy is released from the one or more at least partially deformable portions in response to the first degree of deformation.

208. The system of claim 207, wherein the second effective amount of the at least one therapy is released from the one or more at least partially deformable portions in response to the second degree of deformation.

209. The system of any one of claims 201-208, wherein the at least one other therapy is selected from the group consisting of a β -site amyloid precursor protein cleaving enzyme (BACE) inhibitor, a tau inhibitor, an amyloid immunotherapeutic agent, an amyloid aggregation inhibitor, an anti-inflammatory agent, a neuroprotective agent, an anti-viral agent, a metabolic agent, a thiazolidinedione agent, a neurotransmitter agent, a mitochondrial dynamics modulator, a membrane contact site modifier, a lysosomal function enhancer, an endosomal function enhancer, a transport enhancer, a protein folding modifier, a protein aggregation modifier, a protein stability modifier, and a protein processing modifier.

210. The system of claim 209, wherein the amyloid immunotherapeutic agent is an anti-amyloid antibody.

211. The system of claim 210, wherein the anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb 158.

212. The system of claim 211, wherein the humanized version of mouse monoclonal antibody mAb158 is an IgG1 antibody.

213. The system of claim 212, wherein the IgG1 antibody is BAN 2401.

214. The system of claim 210, wherein the anti-amyloid antibody is a human anti-amyloid antibody.

215. The system of claim 214, wherein the human anti-amyloid antibody is aducartuzumab.

216. The system of any one of claims 201-215, wherein the at least one other therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid β protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

217. The system of any one of claims 201-216, wherein the other therapy is provided at a first dose that is lower than a second dose provided without the device.

218. The system of any one of claims 201-217, wherein the other therapy is provided at a first dosage regimen that is less than a second dosage regimen provided without the device.

219. The system of any one of claims 201-218, wherein the other therapy is provided via a first pathway different from a second pathway provided without the device.

220. The system of any one of claims 201-219, wherein the other therapy is provided by administering the other therapy to a subject in need thereof.

221. The system of claim 210, wherein the additional therapy is administered to the subject in need thereof by eluting the additional therapy from at least a portion of the device.

222. The system of any one of claims 201-221, wherein the disorder is neurodegeneration.

223. The system of claim 222, wherein neurodegeneration further comprises alzheimer's disease, dementia, and/or cognitive disorders.

224. The system as claimed in any one of claims 201-223, wherein the inner and/or outer surface has a substantially cylindrical shape or an undulating shape undulating in a longitudinal direction.

225. The system of any one of claims 201-222, wherein the device has a low profile state and a deployed state, and the sidewall is substantially tubular when in the deployed state.

226. The system of any one of claims 201-223, wherein the mitigating substance is configured to expand in response to an increase in the intravascular blood pressure and relax with a subsequent decrease in the intravascular blood pressure.

227. The system of claim 224, wherein the flexible damping member applies stress at the first location along the length of the tubular structure when positioned in apposition with the blood vessel and a pulse wave travels through the blood vessel.

228. The system of claim 225 wherein at least a portion of the mitigating substance moves longitudinally and/or radially along the length of the tubular structure after the stress is applied at the first location.

229. The system of claim 226 wherein upon application of the stress at the first location, at least a portion of the mitigating substance is configured to move longitudinally and/or radially from a first location within a first deformable portion of the flexible damping member to a second location within the first deformable portion.

230. The system of claim 227, wherein at least a portion of the mitigating substance is further configured to move longitudinally and/or radially within a second deformable portion of the flexible damping member from the first position to a third position upon application of the stress at the first position.

231. The system of any one of claims 201-228, wherein the flexible damping member is further configured to position around at least a portion of the perimeter of the vessel wall, and a pulse wave traveling through the vessel applies stress to a first region of the damping member, at least a portion of the mitigating material moving away from the first region to a second region of the damping member, such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal to the device.

232. The system of any one of claims 201-229, wherein the device is further configured to deploy within the lumen of the blood vessel such that an outer surface of an anchoring member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the sidewall is in contact with blood flowing through the lumen of the blood vessel.

233. The system of claim 230, wherein when the device is deployed within the lumen of the blood vessel and a pulse wave traveling through the blood vessel applies stress on the damping member at the third location, at least a portion of the mitigating substance moves away from the damping member at the third location to a fourth location such that the damping member absorbs at least a portion of the energy of the pulse wave, thereby reducing the stress on the vessel wall distal of the device.

Technical Field

The present technology relates to combination therapies including implantable damping devices and therapeutic agents for treating disorders (e.g., neurodegenerative disorders such as dementia) and related systems and methods of use. In particular, the present technology relates to combination therapies that include an implantable damping device and one or more therapeutic agents (e.g., drugs) for treating a condition, the location of which is disposed at, near, within, around, or in place of at least a portion of an artery.

Background

The heart supplies oxygenated blood to the body through a network of interconnected branched arteries starting from the largest artery-aorta in the body. As shown in the schematic representation of the heart and selected arteries in fig. 1A, the portion of the aorta closest to the heart is divided into three regions: the ascending aorta (the position where the aorta initially extends upward away from the heart), the aortic arch, and the descending aorta (the position where the aorta extends downward). Three major arteries branch from the aorta along the aortic arch: brachiocephalic artery, left common carotid artery, and left subclavian artery. The brachiocephalic artery extends away from the aortic arch and then divides into the right common carotid artery, which supplies oxygenated blood to the head and neck, and the right subclavian artery, which supplies blood primarily to the right arm. The left common carotid artery extends away from the aortic arch and feeds the head and neck. The left subclavian artery extends away from the aortic arch and supplies blood primarily to the left arm. The right and left common carotid arteries then branch into separate internal and external carotid arteries, respectively.

During the systolic phase of the heartbeat, the contraction of the left ventricle forces blood into the ascending aorta, which increases the pressure within the arteries (known as the systolic pressure). The volume of blood ejected from the left ventricle creates a pressure wave-known as a pulse wave-that propagates through the arteries pushing the blood. The pulse waveguide actuates pulse dilation as schematically shown in fig. 1B. When the left ventricle relaxes (the diastolic phase of the heart beat), the pressure within the arterial system decreases (called diastolic pressure), which causes the artery to contract.

The difference between systolic and diastolic pressure is "pulse pressure," which is generally determined by, among other factors, the magnitude of the systolic force produced by the heart, the heart rate, the peripheral vascular resistance, and the diastolic "run-off" (e.g., blood flowing along a pressure gradient from an artery to a vein). High flow organs (such as the brain) are particularly sensitive to excessive pressure and flow pulsations. To ensure that the flow velocities of these sensitive organs are relatively uniform, the arterial vessel wall expands and contracts in response to pressure waves to absorb some of the pulse wave energy. However, as the vasculature ages, the arterial wall loses elasticity, which results in increased pulse wave velocity and wave reflections through the arterial vasculature. Arteriosclerosis impairs the ability of the carotid and other major arteries to dilate and suppress the flow pulsations, resulting in increased systolic and pulse pressures. Thus, over time the arterial wall hardens, the artery transmits excessive force to the distal branch of the arterial vasculature.

Studies have shown that sustained high systolic pressure, pulse pressure, and/or pressure changes over time (dP/dt) increase the risk of dementia, such as vascular dementia (e.g., impaired cerebral blood supply or intracerebral hemorrhage). Without being bound by theory, high vascular pressure is believed to be a possible root cause or exacerbation factor for vascular dementia and age-related dementia (e.g., alzheimer's disease). Thus, the progression of vascular dementia and age-related dementia (e.g., alzheimer's disease) may also be affected by loss of elasticity of the arterial wall and the resulting cerebral vascular pressure. For example, alzheimer's disease is generally associated with the presence of neuritic plaques and tangles in the brain. Recent studies have shown that over time, increased pulse pressure, increased systolic pressure, and/or increased rate of pressure change (dP/dt) may lead to microhemorrhages in the brain, which may lead to neuritic plaques and tangles.

By 2050, it was estimated that at least one of every 85 people worldwide will have alzheimer's disease, and that more than 8 times as many people have shown preclinical symptoms. Additional disease-modifying therapies have been and are being developed that will prevent or delay the onset or slow progression of neurological disorders such as dementia. By 1 month 2018, there are 112 therapeutic agents in clinical trials and/or other relevant tests to treat alzheimer's disease, one of several neurological disorders that are becoming more common as the world population ages. While these therapeutic agents may improve memory, behavior, cognition, and/or reduce the neuropsychiatric symptoms of alzheimer's disease, additional studies testing the efficacy, safety, and tolerability of these therapeutic agents, and/or additional therapeutic agents, are needed. Accordingly, there is a need for improved devices, systems, and methods for treating vascular and/or age-related dementia.

Drawings

Many aspects of the disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Emphasis instead being placed upon clearly illustrating the principles of the present disclosure.

FIG. 1A is a schematic diagram of a portion of a human heart and an arterial system in the vicinity of the heart.

Fig. 1B is a schematic diagram of a pulse wave propagating along a blood vessel.

FIG. 2A is a perspective view of another embodiment of a damping device according to the present technology.

Figure 2B is a cross-sectional view of the damping device shown in figure 2A taken along line 2B-2B.

FIG. 3A is a perspective view of another embodiment of a damping device according to the present technology.

Fig. 3B is a front view of the damping device shown in fig. 4A shown in a deployed state with the position disposed around a blood vessel.

FIG. 4A is a perspective view of a damping device according to another embodiment of the present technology shown in an unwrapped state.

Fig. 4B is a top view of the damping device shown in fig. 4A shown in an unwrapped state.

FIG. 5 is a flow chart illustrating a method in accordance with the present technology.

Detailed Description

The present technology relates to combination therapies comprising an implantable damping device and a therapeutic agent (e.g., a drug) for treating or slowing the progression of a condition, including neurological conditions such as dementia (e.g., vascular dementia and age-related dementia), and related systems and methods of use. For example, some embodiments of the present technology relate to devices and drug combination therapies including a damping device having an anchoring member and a flexible, compliant damping member having an outer surface and an inner surface defining a lumen configured to direct blood flow. The inner surface is configured such that a cross-sectional dimension of the cavity varies. For example, the outer and inner surfaces may be separated from each other by a distance that varies along the length of the damping member. The damping member may also include a first end, a second end opposite the first end, and a damping region between the first end and the second end. The distance between the outer surface and the inner surface of the damping member may be greater at the damping region than at either the first end or the second end. As blood flows through the damping member during systole, the damping member absorbs a portion of the pulsatile energy of the blood to reduce the magnitude of the pulse pressure transmitted to a portion of the blood vessel distal to the damping device. For example, additional embodiments of the present technology relate to devices and drug combination therapies, including therapeutic agents (e.g., drugs) that have been developed or are currently being developed to treat or otherwise mitigate the effects of neurological conditions. These therapeutic agents, and other therapeutic agents derived from and/or otherwise based on these therapeutic agents, are included in embodiments of the present technology. Specific details of several embodiments of the present technology are described below with reference to fig. 1A-5.

With respect to the terms "distal" and "proximal" in this specification, unless otherwise indicated, the terms may refer to an operator, a direction of blood flow through a blood vessel, and/or a location in the vasculature to provide a relative position of a portion of the damping device and/or an associated delivery device. For example, in reference to a delivery catheter adapted for delivering and positioning the locations of the various damping devices described herein, "proximal" refers to a location closer to an operator of the device or an incision into the vasculature, while "distal" refers to a location further from an operator of the device or further from an incision along the vasculature (e.g., the tip of the catheter).

As used herein, "artery" and "artery supplying blood to the brain" include any arterial vessel (or portion thereof) that provides oxygenated blood to the brain. For example, "artery" or "artery supplying blood to the brain" may include the ascending aorta, the aortic arch, the brachiocephalic trunk, the right common carotid artery, the left and right internal carotid arteries, the left and right external carotid arteries, and/or any branch and/or extension of any of the arterial vessels described above.

With respect to the term "neurological disorder" in this specification, unless otherwise indicated, the term refers to a disorder, and/or disease of the brain, spine, and nerves connecting the brain and spine. Neurological disorders include, but are not limited to, dementia (e.g., vascularity, frontotemporal lobe, lewy body), alzheimer's disease, huntington's disease, cognitive disorders, parkinson's disease, neuralgia, tumors, cancer, stroke, aneurysm, epilepsy, headache, and/or migraine.

The term "treating" in relation to a given condition, disease, or disorder includes, but is not limited to, inhibiting the disease or disorder, e.g., inhibiting the development of the condition, disease, or disorder; alleviating the condition, disease, or disorder, e.g., causing regression of the condition, disease, or disorder; or alleviating a condition caused by or resulting from a disease or disorder, e.g., alleviating, preventing, or treating symptoms of a disease or disorder.

The term "prevention" in relation to a given condition, disease, or disorder means: if not already occurring, preventing the onset of its development; preventing the occurrence of the condition, disease, or disorder in a subject who may be predisposed to the condition, disease, or disorder but has not yet been diagnosed as having the condition, disease, or disorder; and/or preventing further development of the condition, disease, or disorder, if already present.

As used herein, a "route" in connection with the administration of one or more therapies, such as a therapeutic agent (e.g., a drug), refers to a route by which the therapeutic agent is delivered to a subject (e.g., the body of the subject). Therapeutic routes of administration include enteral and parenteral routes of administration. Enteral administration includes oral, rectal, enteral, and/or enema. Parenteral includes topical, transdermal, epidural, intracerebral, intracerebroventricular, epidermal (epicutaneous), sublingual, sublabial, buccal, inhalation (e.g., nasal), intravenous, intraarticular, intracardiac, intradermal, intramuscular, intraocular, intraosseous infusion, intraperitoneal, intrathecal, intravitreal, subcutaneous, perivascular, implant, vaginal, otic, and/or transmucosal.

Unless expressly stated otherwise, the use of numerical values in the various quantitative values specified in this application are stated as approximations as if the minimum and maximum values within the stated ranges were all preceded by the word "about". In this way, slight variations from the values can be used to achieve substantially the same results as the values. Further, the disclosure of a range is intended as a continuous range including every value between the recited minimum and maximum values, as well as any range that can be formed from these values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that may be formed by dividing a recited value by any other recited value. Thus, the skilled artisan will appreciate that many such ratios, ranges, and ratio ranges can be explicitly derived from the numerical values presented herein; and in all cases, such ratios, ranges, and ratio ranges are representative of various embodiments of the present invention. Unless otherwise specified, the term "about" refers to a value that is within 10% of the stated value.

While the present invention is capable of embodiment in various forms, the following description of several embodiments is provided with the understanding that the present disclosure is to be considered an exemplification of the invention and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and should not be construed as limiting the invention in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

I.Intravascular embodiments of selected damping devices

Figure 2A is a perspective cross-sectional view of a damping device 200 according to the present technology in an expanded, relaxed state. Fig. 2B is a cross-sectional view of the damping device 200 positionally set in the artery a during transmission of the pulse wave PW through the portion of the artery a surrounded by the damping device 200. Referring to fig. 2A and 2B together, the damping device 200 includes a damping member 202 and a structural member 204 coupled to the damping member 202. Damping member 202 may be a flexible, viscoelastic damping member (e.g., a cushioning member). As shown in fig. 2A, the damping device 200 may have a generally cylindrical shape in an expanded, relaxed state. The damping device 200 may be configured to wrap around the perimeter of an artery with opposing longitudinal edges (not shown) secured to one another via sutures, staples (staples), adhesive, and/or other suitable coupling devices. Alternatively, the damping device 200 may have a longitudinal slit for receiving an artery therethrough. In any of the foregoing extravascular embodiments, the damping device 200 is configured to position it around the perimeter of the artery a such that the inner surface 212 (fig. 2B) is adjacent to and/or in contact with the outer surface of the artery wall. In other embodiments, the damping device 200 may be configured to be positioned within a vessel (e.g., within an arterial lumen) such that the outer surface of the damping device 200 is adjacent to and/or in contact with the inner surface of the arterial wall. In such an intravascular embodiment, the inner surface 212 of the damping member 202 is adjacent to or in direct contact with the blood flowing through the artery a.

The structural member 204 may be a generally cylindrical structure configured to expand from a low-profile state to a deployed state. The structural member 204 is configured to provide structural support to secure the damping device 200 to a selected region of an artery. In some embodiments, the structural member 204 can be a stent formed from a laser cut metal, such as a superelastic and/or shape memory material (e.g., nitinol) or stainless steel. All or a portion of the structural member 204 may include a radiopaque coating to improve visualization of the device 200 during delivery, and/or the structural member 204 may include one or more radiopaque markers. In other embodiments, the structural member 204 may comprise a mesh or woven (e.g., braided) construction in addition to or in lieu of a laser cut stent. For example, the structural member 204 may comprise a tube or a braided mesh formed from a plurality of flexible wires or filaments arranged in a diamond pattern or other configuration. In some embodiments, all or a portion of the structural member 204 may be covered with a graft material (e.g., dacron) to facilitate sealing with the vessel wall. Additionally, all or a portion of the structural member 204 may include one or more biomaterials.

In the embodiment shown in fig. 2A and 2B, the location of the structural member 204 is located radially outward of the damping member 202 and extends along the entire length of the damping member 202 (although the middle portion of the structural member 204 is cut away in fig. 2A for illustrative purposes only). In other embodiments, the structural member 204 and the damping member 202 may have other suitable configurations. For example, the damping device 200 may include more than one structural member 204 (e.g., two structural members, three structural members, etc.). Additionally, in some embodiments, one or more structural members 204 may extend along only a portion of damping member 202 such that a portion of the length of damping member 202 is not surrounded and/or axially aligned by any portion of structural members 204. Further, in some embodiments, the location of all or a portion of the damping member 202 may be disposed radially outward of all or a portion of the structural member 204.

In the embodiment shown in fig. 2A and 2B, damping member 202 includes a proximal damping element 206a and a distal damping element 206B. Damping member 202 may also include an optional channel (not shown) extending between proximal damping element 206a and distal damping element 206 b. For example, a channel may extend in a longitudinal direction along the damping device 200 and fluidly couple the proximal damping element 206a to the distal damping element 206 b. Damping member 202 may also include a mitigating (absorbing) substance 210 (fig. 2B) configured to deform in response to fluid stress (e.g., blood flow), thereby absorbing at least a portion of the stress. For example, as shown in FIG. 2B, in one embodiment, the mitigating substance 210 includes a plurality of fluid particles F (only one fluid particle is labeled) contained within the proximal damping element 206a, the distal damping element 206B, and the one or more channels 208. As used herein, the term "fluid" refers to liquids and/or gases, while "fluid particles" refers to liquid particles and/or gas particles. In some embodiments, the damping member 202 is a gel and the plurality of fluid particles F are dispersed within a network of solid particles. In other embodiments, damping member 202 may include only fluid particles F (e.g., only gaseous particles, only liquid particles, or only gaseous and liquid particles) contained within the flexible and/or elastic membrane defining proximal damping member 206a, distal damping member 206b, and one or more channels 208. The viscosity and/or composition of the mitigating substance 210 may be the same or may vary along the length and/or perimeter of the damping member 202.

Referring to fig. 2B, the pulse wave PW while traveling through the artery a is at a first axial position L along the length of the damping member 202₁At least a portion of the fluid particles are displaced from the first axial position L along the length of the damping member 202 when the stress is applied (e.g., at the wavefront WF)₁To a second axial position L₂. Thus, at least a portion of the fluid particles are redistributed along the length of the damping member 202 such that the inner diameter ID of the damping member 202 is at the first axial position L₁Is increased with the inner diameter ID at another axial position (e.g.，L₂) And decreases. For example, as the wavefront WF passes through the proximal portion 200a of the device 200, the portion of the artery a aligned with the wavefront WF expands, thereby stressing the proximal damping element 206a and forcing at least some of the fluid particles in the proximal damping element 206a to move distally within the damping member 202. At least some of the displaced fluid particles are forced into the distal damping element 206b, thereby increasing the volume of the distal damping element 206b and decreasing the inner diameter ID of the damping device 200 at the distal portion 200 b. The reduced inner diameter ID of the damping device 200 provides an impedance to the blood flow that absorbs at least a portion of the energy in the pulse wave as the blood flow reaches the distal damping member 206 b. Then as the wavefront WF passes through the distal portion 200b of the device 200, the portion of the artery a aligned with the wavefront WF expands, thereby stressing the distal damping element 206b and forcing at least some of the fluid particles currently in the distal damping element 206b to move proximally within the damping member 202. At least some of the displaced fluid particles are forced into proximal damping element 206a, thereby increasing the volume of proximal damping element 206a and decreasing the inner diameter ID of device 200 at proximal portion 200 a. The movement of the fluid particles in response to the pulse wave and/or the deformation of the damping member 202 absorbs at least a portion of the energy carried by the pulse wave, thereby reducing stress on the arterial wall distal to the device.

As the damping member 202 deforms in response to the pulse waves, the shape of the structural member 204 may remain substantially unchanged, thereby providing support to facilitate redistribution of fluid particles within the damping member 202 and along the damping member 202. In other embodiments, the structural member 204 may also deform in response to local fluid stresses.

In some embodiments, damping member 202 is defined by a single chamber (not shown) that includes moderating substance 210 and a plurality of partitions (not shown) that separate the chamber (not shown) into three fluidly coupled compartments (not shown).

The damping member 202 shown in fig. 2A and 2B is a solid sheet of material that is molded, extruded, or otherwise formed into a desired shape. The damping member 202 may be biocompatible, compliant, and configured to deform in response to local fluid pressure in the arteryViscoelastic material. As the damping member 202 deforms, the damping member 202 absorbs a portion of the pulse pressure. For example, damping member 202 may be made of a biocompatible synthetic elastomer, such as silicone rubber (VMQ), Tufel I and Tufel III elastomers (GE high tech materials, Petzfeld, Mass.),(Sorbothane, Inc., Kent, Ohio), and the like. Damping member 202 may be flexible and resilient such that the inner diameter of damping member 202 increases as the contracting pressure waves propagate therein.

Fig. 3A is a perspective view of another embodiment of a damping device 300 according to the present technology, and fig. 3B is a front view of the damping device 300 shown in a deployed state with the position set around an artery a. Referring to fig. 3A-3B together, the damping device 300 in a deployed, relaxed state includes a generally tubular sidewall 305 defining a cavity. The damping device 300 may be formed from a generally parallelogram shaped element wrapped around a mandrel in a helical configuration and heat set. In other embodiments, the damping device 300 may have other suitable shapes and configurations in the relaxed, non-deployed state. As shown in fig. 3B, in the deployed state, the damping device 300 is configured to wrap helically along or around the perimeter of an artery supplying blood to the brain. The opposing longitudinal edges 307 of the damping device 300 converge in the deployed state to form a helical path along the longitudinal axis of the artery a. The damping device 300 may include any of the coupling devices described herein to secure all or a portion of the opposing longitudinal edges to one another, such as a zip-lock type coupling mechanism, a suture, a staple (staple), an adhesive, and/or other suitable coupling devices.

As shown in FIG. 3A, the sidewall 305 of the damping device 300 includes a structural member 304 and a damping member 302. The structural member 304 may be substantially similar to the structural member 204 shown in fig. 2A and 2B, except that the structural member 304 of fig. 3A and 3B has a helical configuration in the deployed state. The damping member 302 may be substantially similar to any damping member described herein, particularly those described with respect to fig. 4A and 4B. In the embodiment shown in fig. 3A and 3B, the position of the damping member 302 is disposed radially inward of the structural member 304 when the damping device 300 is in the deployed state. In other embodiments, the position of the damping member 302 may be disposed radially outward of the structural member 304 when the damping device 300 is in the deployed state.

The damping device 300 may be configured to wrap around the perimeter of the artery a such that the inner surface 312 (fig. 3A) is adjacent to and/or in contact with the outer surface of the artery wall. In other embodiments, the damping device 300 may be configured to be positioned within a vessel (e.g., within an arterial lumen) such that the outer surface of the damping device 300 is adjacent to and/or in contact with the inner surface of the arterial wall. In such an intravascular embodiment, the inner surface 312 of the damping member 302 is adjacent to or in direct contact with the blood flowing through the artery a.

Fig. 4A and 4B are perspective and top views, respectively, of a damping device 400 that may define one embodiment of the damping device 400 shown in fig. 4A and 4B. In fig. 4A and 4B, the damping device 400 is shown in a relaxed, undeployed state. The damping device 400 includes a damping member 402 having a plurality of chambers 406a, 406b, 406c spaced apart along a longitudinal dimension of the damping device 400 in an undamped state. The chambers 406a, 406b, 406c may be fluidly coupled by a channel 408 extending between adjacent chambers. The damping device 400 may thus operate in a manner similar to the damping device 200, with the mitigating material (not shown in fig. 4A and 4B) in the chambers 406a-c moving through the channel 408 to inflate/deflate the various chambers in response to a pressure wave traveling through the blood vessel. The displacement of the mitigating substance within the chambers 406a-c attenuates the energy of the pulse wave to reduce the effect of the pulse wave on the distal side of the damping device 400.

Selected method associated with selected intravascular embodiments of damping devices

Although not shown in the present application, the present techniques also include methods for positioning the damping device of the present disclosure at a treatment location within an artery (e.g., left and/or right common carotid arteries). A method of positioning the damping device of the present disclosure includes intravascularly advancing a guidewire from an access site (e.g., femoral or radial artery) to a treatment site. The guide catheter may then be advanced along the guidewire until at least the position of the distal portion of the guide catheter is disposed at the treatment site. In these and other embodiments, fast switching techniques may be utilized. In some embodiments, the guide catheter may have a pre-shaped or steerable distal portion to guide the guide catheter through one or more bends in the vasculature.

Image guidance, such as Computed Tomography (CT), fluoroscopy, angiography, intravascular ultrasound (IVUS), Optical Coherence Tomography (OCT), or other suitable guidance modalities, or a combination thereof, may be used to assist a clinician in positioning the damping device 200 and operating the damping device 200. For example, the fluoroscopy system (e.g., including a flat panel detector, x-ray, or c-arm) may be rotated to accurately visualize and identify the target treatment site. In other embodiments, the treatment site may be determined using IVUS, OCT, and/or other suitable image mapping patterns that may associate the target treatment site with identifiable anatomy (e.g., spinal features) and/or a radiopaque scale (e.g., positioned under or on the patient) prior to delivery of the damping device of the present technology. Further, in some embodiments, an image guidance component (e.g., IVUS, OCT) may be integral with and/or run in parallel with the delivery catheter to provide image guidance during placement of the damping device of the present technology.

Once the position of the guiding catheter is set at the treatment site, the guidewire may be withdrawn. The delivery assembly carrying the damping device may then be advanced distally through the guide catheter to the treatment site. In some embodiments, the delivery assembly includes an elongate shaft having an atraumatic distal tip and an expandable member (e.g., an inflatable balloon, an expandable cage (cage), etc.) positioned about a distal portion of the elongate shaft. The damping device may be positioned around the expandable member. Expansion or inflation of the expandable member forces at least a portion of the damping device radially outward into contact with the arterial wall. In some embodiments, the delivery assembly can include a distal expandable member for deploying a distal portion of the damping device, and a proximal expandable member for deploying a proximal portion of the damping device. In other embodiments, the entire length of the damping device can be expanded simultaneously by deploying one or more expandable members.

Once the position of the damping device is set at the treatment site, oxygenated blood ejected from the left ventricle flows through the lumen of the damping member. When blood contacts the damping region of the damping member, the damping region deforms to absorb a portion of the pulsatile energy of the blood, which reduces the magnitude of the pulse pressure transmitted to the portion of the artery distal to the damping device (e.g., the more sensitive cerebral artery). The damping area acts as a pressure limiter that distributes the pressure in the systolic phase of the heart cycle more evenly downstream of the damping device without unduly impairing blood flow through the damping device. Accordingly, the damping device reduces pulsatile stress to downstream portions of the arterial network to prevent or at least partially reduce the clinical manifestations of vascular dementia and/or age-related dementia.

III.Selected therapeutic agents for the treatment of neurological disorders

In addition to providing an implantable damping device, the present techniques also include providing a therapeutic agent for treating a neurological disorder. One of ordinary skill in the art will appreciate that the therapeutic agents discussed herein are illustrative of the types of therapeutic agents in the present technology and that the present technology is not limited to the therapeutic agents specifically discussed herein. For example, therapeutic agents not specifically described herein but falling within the classes of therapeutic agents provided herein and/or treating the neurological disorders discussed herein are included in the present technology.

Therapeutic agents for treating neurological disorders (e.g., neurocognitive and/or neurodegenerative disorders) include those approved by the U.S. food and drug administration ("FDA") for use in human subjects, those currently undergoing clinical trials to study their use in human subjects (e.g., clinical trials managed by FDA or other similar tissues in other countries), preclinical therapeutic agents, and any other therapeutic agent used to treat or intended to treat neurological disorders. Examples of neurological disorders, such as neurocognition, neurodegeneration, or other neurological disorders include, but are not limited to, alzheimer's disease, mild alzheimer's disease, prodromal alzheimer's disease, mild cognitive impairment, cerebral amyloid angiopathy, frontotemporal dementia, vascular dementia, age-related dementia, amyloidosis, lewy body disease, parkinson's disease, huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, friedrich's ataxia, and traumatic brain injury. In some embodiments, these therapeutic agents represent more than one therapeutic class of therapeutic agents, more than one mechanism of action, more than one therapeutic target, and more than one therapeutic purpose.

The therapeutic agents discussed herein have different therapeutic objectives, such as disease modifying therapeutics, symptomatic cognitive enhancers, and/or symptomatic agents that address neuropsychiatric and behavioral changes. For example, disease modifying therapeutics alter the pathophysiology of neurological disorders. For example, a symptomatic therapeutic agent alleviates and/or alleviates symptoms associated with a neurological condition. In some embodiments, the therapeutic agent is a disease modifying therapy and a symptomatic therapy. In some embodiments, the therapeutic agent may include more than one therapeutic agent.

In some embodiments, the therapeutic agents of the present technology are members of a general class of therapeutic agents, including, but not limited to, immunotherapeutic agents, small molecule-based therapeutic agents, large molecule-based therapeutic agents, DNA-based therapeutic agents, RNA-based therapeutic agents, stem cell therapeutic agents, and natural therapeutic agents. Each of these general classes of therapeutic agents includes subclasses having different mechanisms of action and therapeutic effects. As non-limiting examples, immunotherapy-based therapeutic agents may include monoclonal antibodies or antigen-binding fragments thereof, polyclonal antibodies or antigen-binding fragments thereof, antibody-drug conjugates, chimeric antigen receptor ("CAR") T cell therapeutics, T cell receptor ("TCR") therapeutics, and vaccines.

The therapeutic agents discussed herein have different therapeutic targets, activities, and effects. For example, therapeutic agents of the present technology include anti-amyloid self-therapeutics, anti-tau therapeutics, anti-inflammatory therapeutics, neuroprotective therapeutics, neurotransmitter-based therapeutics, metabolic therapeutics, antiviral therapeutics, and regenerative therapeutics. Other types of therapeutic agents include thiazolidinedione agents, neurotransmitter modulators, mitochondrial dynamics modulators, membrane contact site modifiers, lysosomal function enhancers, endosomal function enhancers, transport enhancers, protein folding modifiers, protein aggregation modifiers, protein stability modifiers, and protein processing modifiers. In some embodiments, the therapeutic agent has more than one therapeutic effect. For example, the therapeutic agent has one, two, three, four, five, or more different therapeutic effects. For example, in some embodiments, the therapeutic agent is an anti-amyloid therapy and an anti-tau therapy, or in some embodiments, the therapeutic agent is an anti-amyloid therapy and an anti-inflammatory therapy, or in some embodiments, the therapeutic agent is an anti-amyloid therapy and a neuroprotective therapy, or in some embodiments, the therapeutic agent is a neuroprotective therapy and an anti-viral therapy, or any combination thereof.

In some embodiments, the therapeutic agents of the present technology have different mechanisms of action. In some embodiments, a therapeutic agent is selected for administration to a subject in need thereof based on its mechanism of action. For example, some therapeutic agents for treating neurological disorders (e.g., alzheimer's disease) prevent abnormal cleavage of amyloid precursor protein in the brain of a subject. In some embodiments, the therapeutic agent prevents the expression and/or accumulation of amyloid beta protein (a β) in the brain of the subject. In some embodiments, the therapeutic agent prevents the expression and/or accumulation of tau protein in the brain of the subject. In some embodiments, the therapeutic agent treats alzheimer's disease and other neurological disorders by increasing neurotransmission, reducing inflammation, reducing oxidative stress, reducing ischemia, and/or reducing insulin resistance.

Any of the therapeutic agents described herein, as well as other therapeutic agents that are members of the general classes of therapeutic agents described herein, are administered to a subject in need thereof at a therapeutically effective dose. Without intending to be limited by any particular dose, a therapeutically effective dose is an amount of a therapeutic agent that, when administered to a subject in need thereof, treats or at least partially treats a disorder (e.g., a neurodegenerative disorder) in the subject, reduces or at least partially reduces the effect of the disorder (e.g., a neurodegenerative disorder) in the subject. The therapeutically effective dose of each therapeutic agent is selected based on a variety of factors, including, but not limited to, one or more characteristics of the therapeutic agent (e.g., biological activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (e.g., age, sex, disease type and stage, general physical condition, responsiveness to a given dose, and drug type), and the route of administration.

A. Anti-amyloid self-therapeutic agent

In certain neurological disorders, a β peptides aggregate to form misfolded oligomers and amyloid plaques. For example, in alzheimer's disease, aggregation of multiple isoforms of a β (e.g., a β 42 or a β 40) into pathological structures, such as dimers and/or β sheet fibrils, occurs following, among other factors, increased a β secretion in the plasma of a subject, increased a β in the brain of a subject, and/or decreased a β clearance. Anti-amyloid agents include agents that block, reduce, remove, and/or eliminate a β secretion and/or aggregation in a subject. Anti-amyloid therapeutic agents include, but are not limited to, beta-site amyloid precursor protein cleavage (BACE) inhibitors, anti-amyloid immunotherapeutic agents, and anti-aggregation agents.

BACE inhibitors

BACE inhibitors inhibit the function of BACE, which is a β -secretase enzyme, cleaving Amyloid Precursor Protein (APP), resulting in the release of the C99 fragment. When the C99 fragment is released, the γ -secretion cleaves C99 to form multiple types of a β proteins. Blocking BACE with BACE inhibitors prevents and/or reduces the production and/or accumulation of a β protein by preventing cleavage of APP. A non-exhaustive list of BACE inhibitors includes Abelist (atabecestat) (JNJ-54861911, Janssen), BI 1181181(Boehringer Ingelheim), CNP520(Novartis), CTS-21166(CoMentis), Elenbetstat (Elenbecetat) (E2609, Eisai/Biogen), HPP854(High Point), LY2886721(Eli Lilly), LY3202626(Eli Lilly), Lanabestat (Lanabemesat) (AZD3293, AstraZeneca), PF-05297909(Pfizer), PF-06751979(Pfizer), RG7129(Roche), and Verubecstat (MK-8931, Merck).

Although the BACE inhibitor can be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to 500mg/kg of the subject's body weight. For example, suitable dosages of a BACE inhibitor are between about 0.01mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, suitable doses are about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof) of a BACE inhibitor. In some embodiments, the BACE inhibitor is administered in a fixed dose, e.g., about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, about 5000mg, or higher. In some embodiments, the BACE inhibitor is administered in 1 to 50 doses (e.g., the therapy can be delivered with a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the BACE inhibitor is administered chronically. In some embodiments, the dose of the BACE inhibitor is administered in one or more separate administrations or by continuous infusion.

Anti-amyloid immunotherapeutic agent

Anti-amyloid immunotherapeutics target and clear unwanted aggregation of a β protein. For example, anti-amyloid immunotherapeutics reduce aggregation of a β protein and/or prevent further a β aggregation. Anti-amyloid immunotherapeutics include, for example, antibodies or antigen-binding fragments thereof, such as murine antibodies, chimeric antibodies (e.g., including portions derived from any other species other than human and also derived from human), humanized antibodies, or fully human antibodies that bind to a β (e.g., monomeric, oligomeric, and/or fibrillar forms of a β). A non-exhaustive list of anti-amyloid immunotherapeutics includes, for example, AAB-003 (monoclonal antibody; Janssen), ABvac 40 (active vaccine targeting the C-terminus of A.beta.40; Araclon),ACI-24 (liposome-based vaccine; Janssen), AN-1792 (synthetic A β peptide; Janssen), Aducanyumab (aducanumab) (BIIB 037; Biogen), affitope AD02 (synthetic A β fragment protein; AFFiRiS AG), BAN2401 (humanized version of monoclonal antibody mAb 158; Biogen), Babinituzumab (bapineuzumab) (AAB-001; Janssen), CAD106 (active vaccine; Novartis), Clevelopb (crenizumab) (MAB 5102A; Roche), etanercept (TNF- α and IgG fusion protein; Amgen), GSK 776 (monoclonal antibody; GSK 933),(pooled human plasma antibodies; Baxter), gammenex (immunoglobulin therapy; Grifols), Gantenerumab (Gantenerumab) (RO 4909832; Roche), LY2599666 (antigen-binding fragment of monoclonal antibody; Eli Lilly), LY3002813 (monoclonal antibody; Eli Lilly), Lu AF20513 (active vaccine; Otsuka), MEDI1814 (monoclonal antibody; Eli Lilly), NPT088(IgG1 Fc-GAIM fusion protein; Proclara),10% (intravenous immunoglobulin preparation; Octahama), ponezumab (pneuzumab) (Pfizer), SAR228810 (monoclonal antibody; Sanofi), Sulanguzumab (solarezumab) (LY20162430, Eli Lilly), UB 311 (synthetic peptide vaccine; UnitedNuurosis), and vanutide crisifier (active vaccine; ACC-001, Janssen).

Although the anti-amyloid therapeutic agent may be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.1mg/kg to about 250 mg/kg. For example, the dose is between about 1.0mg/kg and about 50mg/kg, between about 3.0mg/kg and about 40mg/kg, between about 5.0mg/kg and about 30mg/kg, between about 7.0mg/kg and about 25mg/kg, or between about 10mg/kg and about 20 mg/kg. For example, a dose may also include one or more doses of about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, or about 100mg/kg (or any combination thereof). In some embodiments, the anti-amyloid immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, the anti-amyloid therapy is administered in 1 to 50 doses (e.g., the therapy may be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the anti-amyloid immunotherapy is administered chronically. In some embodiments, the dose of the anti-amyloid therapy is administered in one or more separate administrations or by continuous infusion.

Other anti-amyloid aggregation therapeutic agents

Other anti-amyloid aggregation therapeutic agents that block, reduce, remove, and/or eliminate a β aggregation can be administered to a subject in need thereof to treat a disorder. Other anti-amyloid aggregation therapeutics include, but are not limited to, vaccines, small molecules, DNA-based therapeutics, RNA-based therapeutics, and other anti-aggregation compounds. Examples of anti-amyloid aggregation therapeutics include ALZT-OP1 (a combination of cromolyn and ibuprofen; AZTherapies), acitretin (a retinoic acid receptor agonist; Actavis), alzhemed (a taurine variant that inhibits beta-sheet formation; neurohem), argatrostat (an avagat) (an arylsulfonamide gamma-secretase inhibitor; Bristol-Myers Squibb), azirgo (azeligon) (a RAGE inhibitor; Pfizer), bexarotene (a retinoid X receptor agonist; Ligad Pharm.), CHF5074 (a gamma-secretase modulator; Ceresepir^TM) Keqingnuo (clioquinol)(Zinc and copper chelator; Prana), ELND005 (neutralizing toxic oligo-N A beta oligomer; Elan), EVP-0962 (gamma secretase modulators; Forum), elayta (CT1812, simga2 receptor antagonist; Cognition), epigallocatechin gallate (Green tea leaf extract; Taiyo), levoflurbiprofen (flurizan) (selective A beta 42 reducer; Myriad), GV-971 (sodium oligomannose, Shanghai Green Valley Pharm.), 5-15 (cyclic sugar alcohols that act as insulin sensitizers and modulate gamma-secretase; Humanetics), insulin, PBT2 (metalloprotein-attenuating compounds; Prana), PF-06648671 (gamma-secretase modulators; Pfizer), PQ912 (glutaminyl cyclase inhibitors; Probiodurg), bos(IRON-1 enhancer; QR Pharma), sargramostim (sargramostim) (GM-CSF leukine, synthetic granulocyte colony stimulating agent; Genzyme), semagletat (semagacetat) (gamma-secretase inhibitor; Eli Lilly), and thalidomide (Celgene).

Although the anti-amyloid therapeutic agent may be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the anti-amyloid immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, the anti-amyloid therapy is administered in 1 to 50 doses (e.g., the therapy may be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the anti-amyloid immunotherapy is administered chronically. In some embodiments, the dose of the anti-amyloid therapy is administered in one or more separate administrations or by continuous infusion.

B. anti-Tau therapeutic agent

In normal physiology, tau protein regulates the stability of axonal microtubules. In certain neurological disorders, hyperphosphorylation of tau protein results in the entanglement of paired helical filaments and tau-associated neurofibrillary tangles. Anti-tau therapeutics, for example, block, reduce, remove, and/or eliminate tau protein production and/or aggregation, tau protein hyperphosphorylation, paired helical filament tangles, and/or tau-associated neurofibrillary tangles. Anti-tau therapeutics include, but are not limited to, vaccines, antibodies, small molecules, DNA-based therapeutics, RNA-based therapeutics, and anti-aggregation compounds. For example, a non-exhaustive list of immunotherapeutic anti-tau therapeutics includes AADvac-1 (active vaccine; Axon), ABBV-8E12(C2N 8E12, IgG4 monoclonal antibody; AbbVie), ACI-35 (liposome-based vaccine; AC Immune SA), BIIB076 (monoclonal antibody; Biogen), BIIB092 (monoclonal antibody; Biogen), JNJ-63733657 (monoclonal antibody; Janssen), LY3303560 (monoclonal antibody; Eli Lilly), NPT088(IgG1 Fc-GAIM fusion protein; Proclara), RG7345 (monoclonal antibody; Roche), and RO 7105705 (monoclonal antibody; Genentech). A non-exhaustive list of small molecules and RNA-based anti-tau therapeutics includes ANAVEX 2-73 (sigma-1 chaperonin kinase)An animal agent; anavex), BIIB080 (antisense oligonucleotide; biogen), epothilone D (microtubule stabilizer; Bristol-Myers Squibb), LMTM/LMTX^TM(TRx 0237/methylene blue, tau aggregation inhibitor; TauRx), nicotinamide (histone deacetylase inhibitor), nilotinib (tyrosine kinase inhibitor; Georgetown Univ.), TPI287 (tubulin binding and microtubule stabilizing agents; Cortic), and tideglusib (glycogen synthase kinase 3 inhibitor; Zeltia).

Although the anti-tau therapeutic agent may be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the anti-tau immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, anti-tau therapy is administered in 1 to 50 doses (e.g., the therapy may be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the anti-tau immunotherapy is administered chronically. In some embodiments, the dose of anti-tau therapy is administered in one or more separate administrations or by continuous infusion.

C. Neurotransmitter-based therapeutics

Neurotransmitters are endogenous molecules, amino acids, and peptides that affect neuronal signaling. Examples of neurotransmitters include glutamic acid, aspartic acid, γ -aminobutyric acid, glycine, nitric oxide, dopamine, norepinephrine, epinephrine, somatostatin, substance P, adenosine, acetylcholine, and the like.

Neurotransmitter-based therapeutics globally increase the amount or activity of neurotransmitters in neurotransmitters, synaptic junctions, presynaptic neurons, postsynaptic neurons, or any other mechanism designed to increase the amount or activity of neurotransmitters available at synaptic junctions or released in response to electrical events, for example, by providing exogenous neurotransmitters, providing prodrugs of neurotransmitters, increasing the release of neurotransmitters from presynaptic neurons, blocking the reuptake of neurotransmitters, blocking the degradation of neurotransmitters, blocking or reversing the inhibition of neurotransmitter or neurotransmitter receptors, or any other mechanism designed to increase the amount or activity of neurotransmitters. In some embodiments, the neurotransmitter-based therapeutic inhibits acetylcholinesterase and/or butyrylcholinesterase and enhances nicotinic and/or muscarinic acetylcholine receptors. Other embodiments of neurotransmitter-based therapeutics target other neurotransmitters, enzymes, and/or receptors.

In some embodiments, the neurotransmitter-based therapeutic agent reduces, globally or otherwise, the amount or activity of a neurotransmitter at a synaptic junction, in a presynaptic neuron, in a postsynaptic neuron. For example, neurotransmitter-based therapeutics reduce the amount of neurotransmitter available at a synaptic junction or released in response to an electrical event by blocking the release of the neurotransmitter from presynaptic neurons, promoting reuptake of the neurotransmitter, enhancing degradation of the neurotransmitter, enhancing inhibition of the neurotransmitter, neutralizing the neurotransmitter, or blocking the binding receptor of the neurotransmitter. In some embodiments, neurotransmitter-based therapeutics may modulate the activity or effect of neurotransmitters in other ways.

Examples of neurotransmitter-based therapeutics include ABT-288 (histamine H3 receptor antagonist; AbbVie), AVP-786 (sigma-1 receptor agonist and NMDA receptor antagonist; Avanir), AVP-923 (combination of dextromethorphan and quinidine; Avanir), allopregnanolone (allosteric modulator of GABA-alpha receptor), aripiprazole (D2 receptor modulator; Bristol-Myers Squibb), tomoxetine (norepinephrine reuptake inhibitor; Eli Lilly), AXS-05 (dextromethorphan and bupropion; Axsome), BI409306 (phosphodiesterase 9A inhibitor; Boehringer Ingelheim), BI 425809 (glycine transporter I inhibitor; Boehringer Ingelheim), Bexipyridine hydrochloride (cholinergic and adrenergic neurotransmission enhancer; Avukis), biobutyrylcycryeri esterase (NIbrex A esterase inhibitor), epothilone agonist (Oxazol receptor portion 2), CPC-201 (cholinesterase inhibitors and peripheral cholinergic antagonists; Allergan), CX516(ampalax, ampakin; Cortex), DAOIB (NMDA receptor modulators; Changhept Hospital, Taiwan), dexpramipexole (dopamine agonist; Biogen), dimepone (dimebon) (Pf-01913539; Medivation), donepezil (reversible acetylcholinesterase inhibitor), dronabinol (CB1 and CB2 endocannabinoid receptor partial agonists; Johns Hopkins Univ.), escitalopram (serotonin reuptake inhibitor, NIA), GSK239512(GSK), galantamine (cholinesterase inhibitors and allosteric potentiators of nicotinic and nicotinic acetylcholine receptors), idarubidine (muscarinic pyridine) (Lu AE 58354, 5-HT6 receptor antagonists; Otsuka), intepirine (5-HT receptor antagonists; intestin 6 receptor antagonists; Brintovor 6 receptor modulators), Britisol-5-HT 0538 (Myelotide-receptor modulators; Squal receptor modulators; Myelotide-2 a; Myelot receptor modulators), memantine (NMDA antagonist), methylphenidate (dopamine reuptake inhibitor), MK-4305 (suvorexant), dual orexin receptor antagonist; Merck), NS2330 (monoamine reuptake inhibitor; Neurosearch), cannabinones (nabilone) (cannabinoid receptor agent; Sunnybrook), neramexane (neramexane) (NMDA receptor channel blocker; Forest), nicotine, ORM-12741 (alpha-2D adrenergic receptor antagonist; Orion), succinamacridine (acetylcholinesterase inhibitor; Shanghai MHC), PF-05212377(5-HT6 antagonist; Pfizer), PXT864 (combination of baclofen and acamprosate; Pharnext), pimavanserin (pimavanserin) (5-HT2a inverse agonist; Acadia), pimeladine (pimeladine) (melatonin receptor agonist and 5-melatonin-1-HT 1A receptor agonist; Neimazapine (alpha-1 receptor agonist), Neuroxazine (alpha-1 receptor antagonist), riluzole (Sanofi), rivastigmine (rivastigmine) (acetylcholinesterase and butyrylcholinesterase inhibitors; Novartis), rotigotine (dopamine agonist), S38093 (histamine H3 receptor antagonist; Sernier), S47445(AMPA receptor agonist; Cortex), SB 202026 (selective muscarinic M1 receptor agonist), SGS-742 (B) receptor antagonist; Novartis), SUVN-502(5-HT6 antagonist; Suven), SUVN-G3031 (histamine H3 receptor antagonist; Suven), sembragiline (monoamine oxidase B inhibitor; Evotech), sultoprazole (sultrozole) (GABA-alpha receptor agonist; GABA), TAK-071 (muscarinic M1 receptor modulator; Takeda), tacrine (reversible acetylcholinesterase inhibitor; valproate/PfPfyzyme inhibitor; ABzate 1; prozaoren inhibitor; ABzaoret-A reuptase inhibitor; prozaorexin inhibitor; AB5-prozaorexin inhibitor; ABOV-receptor antagonist), and zolpidem (a positive allosteric modulator of the GABA-A receptor; Brasilia Univ. Hospital).

Although the neurotransmitter therapeutic can be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the neurotransmitter immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, neurotransmitter therapy is administered in 1 to 50 doses (e.g., the therapy can be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the neurotransmitter immunotherapy is administered chronically. In some embodiments, the dose of neurotransmitter therapy is administered in one or more separate administrations or by continuous infusion.

D. Anti-inflammatory therapeutic agents

In certain neurological disorders (e.g., alzheimer's disease), microglia are overactive, increasing the production of proinflammatory molecules (e.g., cytokines), resulting in chronic neuroinflammation. Thus, other classes of therapeutic agents include anti-inflammatory therapeutic agents. The anti-inflammatory therapeutic agent reduces or otherwise modulates inflammation, oxidative stress, and/or ischemia associated with the neurological condition. In some embodiments, the present technology includes anti-inflammatory therapeutic agents.

Anti-inflammatory therapeutics include mast cell stabilizers such as cromolyn, cromolyn derivatives, cromolyn analogs, eugenol, nedocromil, pemirolast, olopatadine, aflatoxin, deoxynivalenol, zearalenone, ochratoxin a, fumonisin B1, hydrolyzed fumonisin B1, patulin, or ergotamine. Another useful class of anti-inflammatory therapeutic agents may include non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs include salicylate, propionic acid derivatives, acetic acid derivativesExamples of the compound include enolic acid derivatives, anthranilic acid derivatives, selective COX-2 inhibitors, sulfonanilides (sulfonanilides), and the like. For example, NSAIDs include acetylsalicylic acid, diflunisal, salsalate (salsalsalate), ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, lincomron, hypericin, or figwort (figwort). Further examples of anti-inflammatory therapeutics include ALZT-OP1 (a combination of cromolyn and ibuprofen; AZTherapies), Azeliragon (azeliragon) (TTP488, RAGE antagonist; Pfizer), CHF5074 (NSAID, also a gamma-secretase modulator; Ceresepir), celecoxib (a selective COX-2 inhibitor; Pfizer), epigallocatechin gallate (green tea leaf extract; Taiyo), etanercept (TNF- α inhibitor; Pfizer), GC 021109 (a regulator of microglial activity; GliaCure), GRF6019 (plasma-derived therapy; Alkahest),(Baxter), plus Mumunex (immunoglobulin self-preparation; Grifols), HF0220 (glucocorticoid receptor antagonist; Newron), Pellukast (leukotriene receptor antagonist; IntelGenx), minocycline, Nefurazamod (newapamod) (p38 MAPK. alpha. inhibitor; EIP), NP001 (immunomodulator of inflammatory monocytes/macrophages; Neuraltus),10% (Octapharma), PQ912 (Glutamine cyclase inhibitor; Probiodrug), prednisone (corticosteroid), rofecoxib (selective COX-2 inhibitor; Merck), and thalidomide (Celgene).

Although the anti-inflammatory therapeutic agent may be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the anti-inflammatory immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, the anti-inflammatory therapy is administered in 1 to 50 doses (e.g., the therapy can be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the anti-inflammatory immunotherapy is administered chronically. In some embodiments, the dose of the anti-inflammatory therapy is administered in one or more separate administrations or by continuous infusion.

E. Neuroprotective therapeutic agents

Neuroprotective therapeutic agents are provided by reducing cortisol production, reducing neurodegeneration, enhancing cell signaling and processes, enhancing mitochondrial activity, improving neurogenesis and neuroplasticity, improving neuropsychiatric symptoms, improving synaptic function, improving vascular function, protecting thin fibersCellular processes, inhibition of glutamate transmission and reduction of glutamate excitotoxicity, prevention of infection and inflammation, reduction of cholesterol synthesis, reduction of oxidative stress, reduction of reactive oxygen species, modulation of cAMP, stabilization of protein misfolding, and stimulation of the immune system, thereby protecting neurons and/or other cells or systems of the nervous system from disease pathology. Neuroprotective therapeutic agents include, but are not limited to, amino acids, antiviral agents, angiotensin receptor blockers, apolipoprotein E activators, cAMP activity effectors, estrogen receptor B agonists, glucagon-like peptide 1 receptor agonists, glutamate receptor antagonists, glutamate release inhibitors, granulocyte colony stimulating agents, histone deacetylase inhibitors, HMG-CoA reductase inhibitors, iron chelators, mitochondrial function enhancers, monoamine oxidase B inhibitors, non-statin cholesterol lowering agents, p75 neurotrophic factor receptor ligands, phosphatidylinositol 3-kinase/Akt pathway activators, phosphodiesterase 3 antagonists, phosphodiesterase inhibitors, PPAR-gamma agonists, 5-hydroxytryptamine-6 receptor antagonists, and the like. Examples of neuroprotective therapeutic agents include ethyl eicosapentaenoate (purified form of the omega-3 fatty acid EPA), candesartan (angiotensin receptor blocker), cilostazol (phosphodiesterase 3 antagonist; Otsuka), deferiprone (iron chelator), DHP1401(cAMP activity effector; Daehwa), ID1201 (phosphatidylinositol 3-kinase/Akt pathway activator; Dong), liraglutide (glucagon-like peptide 1 receptor agonist; Novo Nordisk), LM11A-31-BHS (p75 neurotrophic factor receptor ligand; PharmatophiX), L-serine, MLC901(NeuroAiD 901), and so forth^TMII, natural herbs), MP-101 (mitochondrial function enhancers; mediti), nicotinamide (histone deacetylase inhibitor), probucol (non-statin cholesterol lowering agent), rasagiline (monoamine oxidase B inhibitor; teva), riluzole, sargrastim (synthetic granulocyte colony stimulating agent), s-equol (estrogen receptor B agonist; ausio), SLAT (HMG-CoA reductase inhibitors and antioxidants; merck), STA-1 (antioxidant; sinkhar), telmisartan (angiotensin II receptor blocker and PPAR-gamma agonist; boehringer Ingelheim), valacyclovir (antiviral agent), vorinostat (histone deacetylase inhibitor), and sanama(xanamema) (11-HSD1 enzyme inhibitor; Actinogen).

Although the neuroprotective therapeutic agent can be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the neuroprotective immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, the neuroprotective therapy is administered in 1 to 50 doses (e.g., the therapy can be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the neuroprotective immunotherapy is administered chronically. In some embodiments, the dose of neuroprotective therapy is administered in one or more separate administrations or by continuous infusion.

F. Metabolic therapeutic agents

Metabolic therapeutics, for example, reduce inflammation, reduce oxidative stress, and prevent ischemia, and thereby alter one or more cellular pathways, alter cellular plasticity, enhance cellular signaling and neurogenesis, enhance mitochondrial activity, improve cellular processes, improve synaptic dysfunction, improve vascular function, inactivate reactive oxygen species, increase insulin signaling, reduce neuronal hyperactivity, and/or modulate cAMP function. Metabolic therapeutics include, but are not limited to, angiotensin receptor blockers, anticonvulsants, β 2 adrenergic receptor agonists, GABA receptor modulators, glucagon-like peptide 1 receptor agonists, insulin-based therapeutics, monoamine oxidase B inhibitors, protein kinase C modulators, selective p38 MAPK α inhibitors, sigma-2 receptor modulators, thiamine-based therapeutics, tyrosine kinase Fyn inhibitors, phosphodiesterase 3 antagonists, phosphatidylinositol 3-kinase/Akt pathway activators, vaccines, and the like. Examples of metabolic therapeutics include allopregnanolone (GABA receptor modulator), benfotiamine (synthetic thiamine), bryostatin 1 (protein kinase C modulator; Neurotrope), cilostazol (phosphodiesterase type 3 inhibitor), CT1812 (sigma-2 receptor modulator; Cognition), DHP1401(cAMP activity effector; Daehwa), formoterol (beta 2 adrenergic receptor agonist; Mylan), GV1001 (telomerase reverse transcriptase peptide vaccine; GemVax), Yoghrine (concentrated human insulin; Eli Lilly), ID1201 (phosphatidylinositol 3-kinase/Akt pathway activator; IlDong), insulin, levetiracetam (anticonvulsant), liraglutide (glucagon-like peptide 1 receptor agonist), oxaloacetic acid (mitochondrial enhancer), rasagiline (monoamine oxidase inhibitor), Secatinib (Fyn 0530, tyrosine kinase inhibitor; Zeneca), and VX-745 (Navratimod, a selective p38 MAPK α inhibitor; EIP).

Although the metabolic therapeutic agent can be administered at any therapeutically effective dose effective to treat a subject in need thereof, the dose ranges from about 0.0001 to about 500mg/kg of body weight. For example, the dose is between about 0.1mg/kg and about 500mg/kg, between about 0.1mg/kg and about 250mg/kg, between about 0.1mg/kg and about 100mg/kg, between about 0.1mg/kg and about 50mg/kg, or between about 0.1mg/kg and about 25 mg/kg. For example, a dose also includes one or more doses of about 0.1mg/kg, about 0.2mg/kg, about 0.3mg/kg, about 0.4mg/kg, about 0.5mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 3.0mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/kg, about 100mg/kg, about 200mg/kg, about 300mg/kg, about 400mg/kg, or about 500mg/kg (or any combination thereof). In some embodiments, the metabolic immunotherapy is administered at a fixed dose of about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 500mg, about 1000mg, or higher. For example, metabolic therapy is administered in 1 to 50 doses (e.g., the therapy can be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25mg to about 5000mg or more, about 50mg to about 2500mg, about 50mg to about 2000mg, about 50mg to about 1500mg, about 50mg to about 1000mg, about 50mg to about 500mg, about 50mg to about 100mg, or any other range that has a therapeutic effect on the symptoms of the subject. For example, the total dose administered may be about 25mg, about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 1000mg, about 1200mg, about 1500mg, about 1800mg, about 2000mg, about 2500mg, about 3000mg, about 4000mg, about 5000mg, or higher. In some embodiments, the metabolic immunotherapy is administered chronically. In some embodiments, the dose of metabolic therapy is administered in one or more separate administrations or by continuous infusion.

G. Antiviral therapeutic agent

Antiviral therapeutics prevent, reduce, and/or eliminate aggregation of a β or tau protein and include, but are not limited to, valacyclovir. The antiviral therapeutic agent is administered at a dose effective to treat the neurological disorder in the subject. The dose may be administered in one or more administrations or by continuous infusion. The dosage range is from about 0.001mg/kg to about 500mg/kg or higher. In some embodiments, a fixed dose may be provided, such as about 100mg, about 200mg, about 300mg, about 400mg, or about 500 mg.

H. Regenerative therapeutic agent

Regenerative therapeutics enhance neuroplasticity, promote neurogenesis, and/or regenerate neurons. In some embodiments, regenerative therapies include, but are not limited to, immunotherapy, small molecule agents, stem cell therapy, and growth factors. Stem cell therapies include, for example, human mesenchymal stem cells. Examples of regenerative therapies include AstroStem (autologous adipose tissue-derived mesenchymal stem cells; Nature Cell Co.), CB-AC-02 (placenta-derived MSC; CHA Biotech), hUCB-MSC (Stem Cell therapy; Medipost), hMSC (Stem Cell therapy; Longeveron), and NDX-1017 (hepatocyte growth factor; M3).

The regenerative therapeutic agent is administered at a dose effective to treat the neurological disorder in the subject. The dose may be administered in one or more administrations or by continuous infusion. The dose ranges from about 100 million to about 2.5 million stem cells. In some embodiments, the dose is from about 1000 to about 2 million stem cells, from about 1500 to about 1.5 million stem cells, or from about 2000 to about 1 million stem cells.

I. Additional therapeutic agents

An additional therapeutic agent for treating a condition in a subject according to the present technology is aducamumab, an anti-amyloid immunotherapy. Aducarinumab is a high affinity, fully human IgG1 monoclonal antibody that binds to a β conformational epitope on a β oligomeric and fibrillar forms to prevent and/or reduce a β aggregation. In some embodiments, the aducamumab is administered in multiple doses per month, such as between about 0.1mg/kg and about 75mg/kg, between about 1mg/kg and about 60mg/kg, between about 1mg/kg and about 15mg/kg, or between about 1mg/kg and/or about 10 mg/kg. In some embodiments, the aducamumab is administered at a dose of about 1mg/kg, about 3mg/kg, about 6mg/kg, about 10mg/kg, about 30mg/kg, or about 60 mg/kg. Repeated doses of adolesomamab may be constant (e.g., a monthly dose of about 3mg/kg), or may be escalating (e.g., about 1mg/kg at month 1, about 3mg/kg at months 2-4, about 6mg/kg at month 510, and about 10mg/kg at month 11 and 12). In some embodiments, the adalimumab is administered for a period of one year. In other embodiments, the aducartuzumab is administered chronically.

Another additional therapeutic agent for treating a condition in a subject according to the present technology is BAN 2401. BAN2401 is a humanized IgG1 monoclonal antibody that binds to a β fibrils. Infusion or other administration of BAN2401 may be daily, weekly, biweekly, monthly, or any other plan designed to achieve a therapeutic effect on a subject in need thereof. In some embodiments, BAN2401 is administered once every two weeks. In some embodiments, the dose of BAN2401 is selected from the range of about 1mg/kg to about 50mg/kg, about 2mg/kg to about 25mg/kg, and/or about 2.5mg/kg to about 10 mg/kg. In some embodiments, BAN2401 is administered at a dose of about 2.5mg/kg, about 5mg/kg, or about 10 mg/kg. In some embodiments, BAN2401 is administered for a period of between about four months to about one year. In some embodiments, BAN2401 is administered chronically.

Those skilled in the art will appreciate that the foregoing therapies and accompanying descriptions are for illustrative purposes and do not limit the therapies that may be provided in certain embodiments of the present technology. Thus, any therapy for or designed to treat a neurological disorder (e.g., a neurodegenerative disorder) may be present in certain embodiments of the present technology.

Selected methods of treating neurological disorders using a combination of an implantable damping device and a therapeutic agent

Reducing the subject's pulse pressure with an implantable damping device has subsequent downstream effects on other factors that lead to the onset, duration, and/or progression of a disorder (e.g., a neurological disorder) in the subject, such as, but not limited to, increased sRAGE expression, decreased plasma and brain amyloid β levels, and decreased tau protein levels. These factors lead to, among other things, inflammation, oxidative stress, ischemia and insulin resistance, which in turn leads to dysfunction of synapses and/or neurons and impaired neurotransmission. This occurs in subjects with disorders such as progressive cognitive dysfunction and dementia.

Several biological pathways, such as those described herein, may contribute to neurological disorders (e.g., dementia). Without intending to be bound by any particular theory, it is believed that interfering with (e.g., altering, affecting, impairing, inhibiting, reducing, or otherwise altering the function of) two or more biological pathways is more effective to treat, prevent, or otherwise alleviate a neurological disorder and/or symptoms thereof in a subject, rather than interfering with a single biological pathway. In this way, the effects of combining the implantable damping device of the present technology and the at least one therapeutic agent can be complementary, additive, or even synergistic when compared to the effects of the implantable damping device and the therapeutic agent alone. Thus, the implantable damping device is combined with one or more therapeutic agents that affect these other factors to further treat and/or mitigate one or more effects of the condition.

As noted above, the combination therapies of the present technology include an implantable damping device and a therapeutic agent (e.g., a drug) for treating or slowing the progression of the condition. For example, some embodiments of the present technology relate to combination therapies comprising an implantable damping device as described above under headings I-III and one or more therapeutic agents targeting these factors. Some of these therapeutic agents are described above under title IV, including, but not limited to, BACE inhibitors, anti-amyloid immunotherapy, anti-amyloid aggregation therapy, anti-tau therapy, neurotransmitter-based therapy, neuroprotective and/or anti-inflammatory therapy, metabolic therapy, and antiviral therapy. When combined, the implantable damping devices and therapeutic agents of the present technology have greater effects in treating or mitigating the effects of one or more conditions on a subject than the effects of the implantable damping devices or therapeutic agents alone. For example, providing an implantable damping device that reduces pulse pressure in a subject and an anti-amyloid therapy that reduces amyloid formation in the brain and blood vessel walls of a subject improves synapses and/or neuronal function and neurotransmission, thereby treating or slowing progressive cognitive dysfunction and dementia.

Fig. 5 is a flow diagram illustrating a method 500 for treating or alleviating one or more effects of a disorder in a subject. At block 520, the method 500 provides a means for treating or alleviating one or more effects of the disorder. The device is an implantable damping device of the present technology and is configured to be placed in apposition to a blood vessel of a subject. Similar to other devices of the present technology, the device provided in method 500 includes a flexible damping member having an inner surface formed by a sidewall having one or more at least partially deformable portions and an outer surface. Further, a mitigating substance is disposed within the partially deformable portion and is configured to move longitudinally and/or radially therein in response to pulsatile blood flow within the blood vessel. At block 560, the method 500 provides at least one additional therapy in combination with the implantable damping device to treat or mitigate one or more effects of the condition. In some embodiments, the additional therapy is provided to the subject for up to about 24 hours, up to about 7 days, up to about 4 weeks, up to about 12 months, or up to about 5 years prior to implantation of the damping device. In other embodiments, the implantable damping device is provided to the subject for up to about 24 hours, up to about 7 days, up to about 4 weeks, up to about 12 months, or up to about 5 years prior to other therapies. For example, the other therapy (e.g., therapeutic agent) or the implantable damping device is provided to the subject about 0 to about 24 hours, about 1 to about 5 hours, about 3 to about 12 hours, about 5 to about 10 hours, about 1 day to about 7 days, about 2 days to about 6 days, about 3 days to about 5 days, about 1 week to about 4 weeks, about 2 weeks to about 4 weeks, about 1 week to about 3 weeks, about 2 weeks to about 3 weeks, about 1 year to about 5 years, about 1 year to about 4 years, about 2 years to about 5 years, about 2 years to about 4 years, about 3 years to about 4 years, or about 4 years to about 5 years, respectively, before the damping device or the other therapy (e.g., therapeutic agent) is implantable.

As described above under title III, at least one other therapy of the methods of the present technology is provided to the subject by administration. In some embodiments, the other therapy (e.g., therapeutic agent) is selected from BACE inhibitors, tau inhibitors, amyloid immunotherapeutic agents, amyloid aggregation inhibitors, anti-inflammatory agents, neuroprotective agents, antiviral agents, metabolic agents, thiazolidinedione agents, neurotransmitter agents, mitochondrial dynamics modulators, membrane contact site modifiers, lysosomal function enhancers, endosomal function enhancers, trafficking enhancers, protein folding modifiers, protein aggregation modifiers, protein stability modifiers, and protein processing modifiers. In some embodiments, the amyloid immunotherapeutic agent is an anti-amyloid antibody. The anti-amyloid antibody is a humanized version of mouse monoclonal antibody mAb158, e.g., an IgG1 antibody, such as BAN2401, or a human anti-amyloid antibody, such as aducarinumab. In some embodiments, the at least one additional therapy prevents abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents expression and/or accumulation of amyloid beta protein in the brain of the subject, prevents expression and/or accumulation of tau protein in the brain of the subject, increases neurotransmission, reduces inflammation, reduces oxidative stress, reduces ischemia, and/or reduces insulin resistance.

When combined with an implantable damping device of the present technology, the therapeutic agents described herein are provided at a first dose that is lower than a second dose of the same therapeutic agent provided in the absence of the implantable damping device (e.g., the subject receives only the therapeutic agent, rather than being used in combination with the implantable damping device). For example, a subject having a neurodegenerative disorder (e.g., dementia) is provided with a lower dose of BAN2401 before, during, or after being provided with an implantable damping device as compared to a subject provided with a dose of BAN2401 but not an implantable damping device.

In some embodiments, when combined with an implantable damping device of the present technology, a therapeutic agent described herein is provided at a first dosage regimen that is less than a second dosage regimen of the same therapeutic agent provided in the absence of the implantable damping device. For example, a subject having a neurodegenerative disorder (such as dementia) is provided with a first dosing regimen of BAN2401 before, during, or after being provided with an implantable damping device as compared to a subject provided with a second dosing regimen of BAN2401 but not an implantable damping device.

In some embodiments, when combined with the implantable damping devices of the present technology, the therapeutic agents described herein are provided with the therapeutic agent through a first pathway that is different from a second pathway provided in the absence of the implantable damping device. For example, a subject having a neurodegenerative disorder (such as dementia) is provided with BAN2401 via a first route before, during, or after being provided with an implantable damping device, as compared to a subject provided with BAN2401 via a second route but not provided with an implantable damping device. In some embodiments, the route of administration includes delivering the therapeutic agent from the device to the subject, e.g., by eluting a therapeutic agent previously stored in at least a portion of the device.

V.Selected systems for treating neurological conditions using a combination of an implantable damping device and a therapeutic agent

In addition to the methods, damping devices, and therapeutic agents described herein, the present technology also includes associated systems for treating or alleviating one or more effects of a condition in a subject. The systems of the present technology include an effective amount of at least one therapy for treating or alleviating one or more effects of a disorder and a device for treating or alleviating one or more effects of a disorder. As set forth above, the devices of the present technology include at least a flexible damping member forming a generally tubular structure having an inner surface formed by a sidewall having one or more at least partially deformable portions, and a mitigating substance disposed therein and configured to move longitudinally and/or radially within one of the partially deformable portions in response to pulsatile blood flow within the blood vessel. In some embodiments, the therapy includes at least one or more therapeutic agents that can be carried by the damping device. In these embodiments, the therapeutic agent is disposed within and/or carried by at least one or more of the at least partially deformable portions of the damping device. An effective amount of the therapeutic agent can be released from the device when one or more of the at least partially deformable portions of the damping device is at least partially deformed.

VI.Examples of the invention

The following examples illustrate several embodiments of the present technology.

A.Example 1

In accordance with the present techniques, the position of the implantable device will be disposed at, near, around, within, or in place of at least a portion of an artery of the subject. After the position of the implantable device has been set, the subject receiving the implantable device will be randomly divided into one of at least two groups: group a-placebo, group B-drug. The placebo will be an experimentally suitable placebo used to distinguish any particular effect of the drug, such as a pharmaceutically acceptable carrier for the active pharmaceutical ingredient ("API") in the drug. The placebo dose is comparable to the amount of pharmaceutically acceptable carrier received by group B subjects. Group B can include two or more subgroups, with subjects being randomly assigned to each subgroup. While each subject in each of these subgroups of group B eventually receives the same drug, the dose, route of administration, dosage regimen, or other parameters associated with the treatment regimen may be varied.

B.Example 2

The drug will be delivered to the subject at a pre-specified dose, route of administration, frequency, duration. After the drug has been delivered to the subject, the subject will be randomized into one of at least two groups: group a-sham surgery (sham), group B-implantable devices. For those subjects in group B, the location of the implantable device will be disposed at, near, around, within, or in place of at least a portion of the subject's artery in accordance with the present techniques. Sham treatment of group a includes delivery methods associated with delivery of implantable devices for group B, although implantable devices will not be delivered to the subjects of group a.

VII. conclusion

While many of the embodiments are described above with respect to systems, devices, and methods for treating and/or slowing the progression of vascular and/or age-related neurological conditions (e.g., dementia) via a combination therapeutic (e.g., drug) and intravascular approach, the techniques are applicable to other applications and/or other approaches, such as surgical implantation of one or more damping devices in combination with one or more drugs and/or treatment of vessels other than the arterial vessels supplying blood to the brain, such as the abdominal aorta. Any suitable site within the vessel may be treated, including, for example, the ascending aorta, the aortic arch, the brachiocephalic artery, the right subclavian artery, the left common carotid artery, the right common carotid artery, the internal carotid artery, and the external carotid artery, and/or branches of any of the foregoing. Moreover, other embodiments in addition to those described herein are also within the scope of the present technology. Additionally, several other embodiments of the present technology may have different configurations, components, or procedures than those described herein. Accordingly, those of ordinary skill in the art will accordingly appreciate that the present techniques may have other embodiments with additional elements or that the present techniques may have other embodiments without several of the features shown and described above with reference to fig. 2A-5.

The above detailed description of embodiments of the present technology is not intended to be exhaustive or to limit the technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include plural or singular terms, respectively. While specific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while the steps are presented in a given order, alternative embodiments may perform the steps in a different order. The various embodiments described herein may also be combined to provide further embodiments.

Furthermore, unless the term "or" is expressly limited in a list relating to two or more items to mean only a single item exclusive of other items, the use of "or" in such a list should be interpreted to include (a) any single item in the list, (b) all items in the list, or (c) any combination of items in the list. Additionally, the term "comprising" is used throughout to mean including at least the recited feature or features, such that any greater number of the same feature and/or additional types of other features are not excluded. It should also be understood that the specific embodiments are described herein for purposes of illustration, but that various modifications may be made without deviating from the present technology. Moreover, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the present disclosure and associated techniques may encompass other embodiments not explicitly shown or described herein.