阅读说明：本技术 Tdp-43相关疾病的预防和治疗 (Prevention and treatment of TDP-43-related diseases ) 是由 E.马科图利 D.阿尔米纳纳 M.莫里斯 R.德林格尔 于 2018-10-19 设计创作，主要内容包括：本文提供了与治疗和/或预防与TDP-43的细胞质积累有关的疾病或病症相关的方法和组合物,所述治疗和/或预防是通过向受试者给予(例如,向受试者口服给予)包含烟酰胺核苷和/或紫檀芪的组合物进行的。(Provided herein are methods and compositions related to treating and/or preventing a disease or disorder associated with cytoplasmic accumulation of TDP-43 by administering to (e.g., orally administering to) a subject a composition comprising nicotinamide riboside and/or pterostilbene.)

1. A method of treating or preventing a disease or disorder associated with cytoplasmic accumulation of TDP-43 in a subject, said subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, said method comprising administering to said subject a composition comprising nicotinamide riboside.

2. A method of treating or preventing a disease or disorder associated with autophagy in a subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, the method comprising administering to the subject a composition comprising nicotinamide riboside.

3. A method of treating or preventing a disease or disorder associated with protein misfolding in a subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, the method comprising administering to the subject a composition comprising nicotinamide riboside.

4. A method of treating or preventing a neurodegenerative disease or disorder in a subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, the method comprising administering to the subject a composition comprising nicotinamide riboside.

5. A method of treating or preventing a disease or disorder in a subject, said subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, said method comprising administering to said subject a composition comprising nicotinamide riboside.

6. The method of any one of claims 1 to 5, wherein the composition further comprises pterostilbene.

7. The method of any one of claims 1 to 5, further comprising administering to the subject a composition comprising pterostilbene.

8. The method of any one of claims 1-7, wherein the disease or disorder is a tauopathy.

9. The method of any one of claims 1 to 8, wherein the disease or disorder is alzheimer's disease, amyotrophic lateral sclerosis, parkinson's dementia complex of guam, myelophagous disease, preggies dementia, chronic traumatic encephalopathy, calcified diffuse neurofibrillary tangles, down's syndrome, familial british dementia, familial danish dementia, frontal dementia, frontotemporal lobular degeneration, Gertmann-Straussler-Scheinker disease, globulo tauopathy, leukotauopathy with globular glial inclusions, Guadeloupean parkinsonism with dementia, gadelopean progressive supranuclear palsy, multiple system atrophy, myotonic dystrophy, neurodegeneration with brain iron accumulation, hallerovorden-Spatz disease, pantothenic kinase related neurodegeneration, neurofibrillary tangle dominant dementia, nieman-Pick disease type C, Pick's disease, forebrain Parkinson disease, prion cerebral amyloid angiopathy, progressive supranuclear palsy, SLC9A 6-related mental retardation or subacute sclerosing panencephalitis.

10. The method of any one of claims 1 to 9, wherein the cells exhibiting accumulation of TDP-43 are neurons.

11. The method of any one of claims 1 to 10, wherein at least 1% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

12. The method of any one of claims 1 to 10, wherein at least 5% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

13. The method of any one of claims 1 to 10, wherein at least 10% of the total cellular TDP-43 in the cell is in the cytoplasm of the cell.

14. The method according to any one of claims 1 to 10, wherein at least 20% of the total cellular TDP-43 in the cell is in the cytoplasm of the cell.

15. The method of any one of claims 1 to 10, wherein at least 30% of all TDP-43 in the cell is in the cytoplasm of the cell.

16. The method of any one of claims 1 to 10, wherein at least 40% of all TDP-43 in the cell is in the cytoplasm of the cell.

17. The method of any one of claims 1 to 10, wherein at least 50% of the total TDP-43 in the cell is in the cytoplasm of the cell.

18. The method of any one of claims 1 to 10, wherein the cells comprise a concentration of cytoplasmic TDP-43 that is greater than the concentration of cytoplasmic TDP-43 present in the same cells in a healthy individual.

19. The method of any one of claims 1 to 18, wherein at least 1% of the neurons in the subject exhibit TDP-43 cytoplasmic accumulation.

20. The method according to any one of claims 1 to 19, wherein the subject comprises a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

21. A method of treating or preventing a disease or disorder associated with cytoplasmic accumulation of TDP-43 in a subject comprising a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation, the method comprising administering to the subject a composition comprising nicotinamide riboside.

22. A method of treating or preventing a disease or disorder associated with autophagy in a subject comprising a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation, the method comprising administering to the subject a composition comprising nicotinamide riboside.

23. A method of treating or preventing a disease or disorder associated with protein misfolding in a subject comprising a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation, the method comprising administering to the subject a composition comprising nicotinamide riboside.

24. A method of treating or preventing a neurodegenerative disease or disorder in a subject comprising a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation, the method comprising administering to the subject a composition comprising nicotinamide riboside.

25. A method of treating or preventing a disease or disorder in a subject, said subject comprising cells exhibiting cytoplasmic accumulation of TDP-43, said method comprising administering to said subject a composition comprising nicotinamide riboside.

26. The method of any one of claims 21 to 25, wherein the composition further comprises pterostilbene.

27. The method of any one of claims 21 to 25, further comprising administering to the subject a composition comprising pterostilbene.

28. The method of any one of claims 21-27, wherein the disease or disorder is a tauopathy.

29. The method of any one of claims 21 to 28, wherein the disease or disorder is alzheimer's disease, amyotrophic lateral sclerosis, parkinson's dementia complex of guam, myelophagous disease, preggies dementia, chronic traumatic encephalopathy, calcified diffuse neurofibrillary tangles, down's syndrome, familial british dementia, familial danish dementia, frontal dementia, frontotemporal lobular degeneration, Gertmann-Straussler-Scheinker disease, globulo tauopathy, leukotauopathy with globular glial inclusions, Guadeloupean parkinsonism with dementia, gadelopean progressive supranuclear palsy, multiple system atrophy, myotonic dystrophy, neurodegeneration with brain iron accumulation, hallerovorden-Spatz disease, pantothenic kinase related neurodegeneration, neurofibrillary tangle dominant dementia, nieman-Pick disease type C, Pick's disease, forebrain Parkinson disease, prion cerebral amyloid angiopathy, progressive supranuclear palsy, SLC9A 6-related mental retardation or subacute sclerosing panencephalitis.

30. The method of any one of claims 21 to 29, wherein the subject comprises cells exhibiting cytoplasmic accumulation of TDP-43.

31. A method of treating or preventing a disease or disorder associated with cytoplasmic accumulation of TDP-43 in a subject, the method comprising:

(a) determining from a sample obtained from the subject whether TDP-43 has accumulated in the cytoplasm of the cell; and

(c) administering to the subject a composition comprising nicotinamide riboside if TDP-43 has accumulated in the cytoplasm of the cell.

32. A method of treating or preventing a disease or disorder associated with autophagy in a subject, the method comprising:

(a) determining from a sample obtained from the subject whether TDP-43 has accumulated in the cytoplasm of the cell; and

(c) administering to the subject a composition comprising nicotinamide riboside if TDP-43 has accumulated in the cytoplasm of the cell.

33. A method of treating or preventing a disease or disorder associated with protein misfolding in a subject, the method comprising:

(a) determining from a sample obtained from the subject whether TDP-43 has accumulated in the cytoplasm of the cell; and

(c) administering to the subject a composition comprising nicotinamide riboside if TDP-43 has accumulated in the cytoplasm of the cell.

34. A method of treating or preventing a neurodegenerative disease or disorder in a subject, the method comprising:

(a) determining from a sample obtained from the subject whether TDP-43 has accumulated in the cytoplasm of the cell; and

(c) administering to the subject a composition comprising nicotinamide riboside if TDP-43 has accumulated in the cytoplasm of the cell.

35. A method of treating or preventing a disease or disorder in a subject, the method comprising:

(a) determining from a sample obtained from the subject whether TDP-43 has accumulated in the cytoplasm of the cell; and

(c) administering to the subject a composition comprising nicotinamide riboside if TDP-43 has accumulated in the cytoplasm of the cell.

36. The method of any one of claims 31 to 35, wherein the composition further comprises pterostilbene.

37. The method of any one of claims 31 to 35, further comprising administering to the subject a composition comprising pterostilbene if TDP-43 has accumulated in the cytoplasm of the subject.

38. The method of any one of claims 31-37, wherein the disease or disorder is a tauopathy.

39. The method of any one of claims 31-38, wherein the disease or disorder is alzheimer's disease, amyotrophic lateral sclerosis, parkinson's dementia complex of guam, myelophagous disease, preggies dementia, chronic traumatic encephalopathy, calcified diffuse neurofibrillary tangles, down's syndrome, familial british dementia, familial danish dementia, frontal dementia, frontotemporal lobular degeneration, Gertmann-Straussler-Scheinker disease, globulo tauopathy, leukotauopathy with globular glial inclusions, Guadeloupean parkinsonism with dementia, gadelopean progressive supranuclear palsy, multiple system atrophy, myotonic dystrophy, neurodegeneration with brain iron accumulation, hallerovorden-Spatz disease, pantothenic kinase related neurodegeneration, neurofibrillary tangle dominant dementia, nieman-Pick disease type C, Pick's disease, forebrain Parkinson disease, prion cerebral amyloid angiopathy, progressive supranuclear palsy, SLC9A 6-related mental retardation or subacute sclerosing panencephalitis.

40. The method of any one of claims 31 to 39, wherein the cells exhibiting accumulation of TDP-43 are neurons.

41. The method of any one of claims 31-40, wherein at least 1% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

42. The method of any one of claims 31-40, wherein at least 5% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

43. The method of any one of claims 31-40, wherein at least 10% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

44. The method of any one of claims 31-40, wherein at least 20% of total cellular TDP-43 in the cell is in the cytoplasm of the cell.

45. The method of any one of claims 31 to 40, wherein at least 30% of all TDP-43 in the cell is in the cytoplasm of the cell.

46. The method of any one of claims 31 to 40, wherein at least 40% of all TDP-43 in the cell is in the cytoplasm of the cell.

47. The method of any one of claims 31 to 40, wherein at least 50% of all TDP-43 in the cell is in the cytoplasm of the cell.

48. The method according to any one of claims 31 to 47, wherein the step of determining the amount of TDP-43 in the cytoplasm comprises contacting cells in the sample with an antibody specific for TDP-43.

49. The method according to any one of claims 31 to 48, wherein the subject comprises a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

50. The method of any one of claims 31-49, wherein the sample comprising cells is a cerebrospinal sample.

51. A method of treating or preventing a disease or disorder associated with cytoplasmic accumulation of TDP-43 in a subject, the method comprising:

(a) determining whether the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation; and

(c) administering a composition comprising nicotinamide riboside to the subject if the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

52. A method of treating or preventing a disease or disorder associated with autophagy in a subject, the method comprising:

(a) determining whether the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation; and

(c) administering a composition comprising nicotinamide riboside to the subject if the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

53. A method of treating or preventing a disease or disorder associated with protein misfolding in a subject, the method comprising:

(a) determining whether the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation; and

(c) administering a composition comprising nicotinamide riboside to the subject if the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

54. A method of treating or preventing a neurodegenerative disease or disorder in a subject, the method comprising:

(a) determining whether the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation; and

(c) administering a composition comprising nicotinamide riboside to the subject if the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

55. A method of treating or preventing a disease or disorder in a subject, the method comprising:

(a) determining whether the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation; and

(c) administering a composition comprising nicotinamide riboside to the subject if the subject carries a pathological form of TDP-43, a variant TDP-43 protein associated with increased cytoplasmic accumulation, or a gene encoding a variant TDP-43 protein associated with increased cytoplasmic accumulation.

56. The method of any one of claims 51-55, wherein the composition further comprises pterostilbene.

57. The method of any one of claims 51-55, further comprising administering to the subject a composition comprising pterostilbene.

58. The method of any one of claims 51-57, wherein the disease or disorder is a tauopathy.

59. The method of any one of claims 51-58, wherein the disease or disorder is Alzheimer's disease, amyotrophic lateral sclerosis, Guam Parkinson dementia syndrome, Chlorophytin, Prgis dementia, chronic traumatic encephalopathy, calcified diffuse neurofibrillary tangles, Down's syndrome, familial British dementia, familial Danish dementia, frontal dementia, frontotemporal lobular degeneration, Gertmann-Straussler-Scheinker disease, globulo tauopathy, leukotauopathy with globular glial inclusions, Guadelupean Parkinson's disease with dementia, Guadeloupean progressive supranuclear palsy, multiple system atrophy, myotonic dystrophy, neurodegeneration with brain iron accumulation, HalLEvorden-Spatz disease, pantothenate kinase-related neurodegeneration, neurofibrillary tangle dominant dementia, Niema-Pick disease type C, Pick's disease, forebrain Parkinson disease, prion cerebral amyloid angiopathy, progressive supranuclear palsy, SLC9A 6-related mental retardation or subacute sclerosing panencephalitis.

60. The method of any one of claims 51-59, wherein the subject comprises cells that exhibit cytoplasmic accumulation of TDP-43.

61. The method of any one of claims 51-60, wherein the gene is a TARDBP gene.

62. The method of any one of claims 51 to 61, wherein the TDP-43 variant has a mutation at its N-terminus.

63. The method of any one of claims 51 to 62, wherein said TDP-43 variant has a truncation mutation.

64. The method of any one of claims 51 to 63, wherein the pathological form is phosphorylated TDP-43.

65. The method of any one of claims 51 to 64, wherein identifying the pathological form of TDP-43 comprises contacting cells in the sample with an antibody specific for the pathological form of TDP-43.

66. A method of selecting a subject for treatment comprising administration of a composition comprising nicotinamide riboside, the method comprising assaying a sample from the subject for the amount of TDP-43 in the cytoplasm of a cell, and selecting the subject for treatment if TDP-43 has accumulated in the cytoplasm of a cell, the treatment comprising administration of a composition comprising nicotinamide riboside.

67. The method of claim 66, wherein the composition further comprises pterostilbene.

68. The method of claim 66 or 67, wherein assaying the cytoplasmic level of TDP-43 comprises contacting the sample with an antibody specific for TDP-43.

69. The method of any one of claims 1 to 68, wherein administering a composition comprises administering one or more doses of the composition.

70. The method of claim 69, wherein each dose of composition comprises at least 800mg nicotinamide riboside.

71. The method of claim 69, wherein each dose of composition comprises at least 1000mg nicotinamide riboside.

72. The method of claim 69, wherein each dose of composition comprises at least 1200mg nicotinamide riboside.

73. The method of claim 69, wherein each dose of composition comprises at least 1400mg nicotinamide riboside.

74. The method of claim 69, wherein each dose of composition comprises at least 1600mg nicotinamide riboside.

75. The method of claim 69, wherein each dose of composition comprises at least 1800mg nicotinamide riboside.

76. The method of claim 69, wherein each dose of composition comprises at least 2000mg nicotinamide riboside.

77. The method of claim 69, wherein each dose of composition comprises at least 2200mg nicotinamide riboside.

78. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 60mg of pterostilbene.

79. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 100mg of pterostilbene.

80. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 200mg of pterostilbene.

81. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 300mg of pterostilbene.

82. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 400mg of pterostilbene.

83. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 500mg of pterostilbene.

84. The method of any one of claims 69 to 77, wherein each dose of composition comprises at least 600mg of pterostilbene.

85. The method of any one of claims 69 to 84, wherein two or more doses of the composition are administered.

86. The method of any one of claims 69 to 84, wherein thirty or more doses of the composition are administered.

87. The method of any one of claims 69 to 84, wherein fifty or more doses of the composition are administered.

88. The method of any one of claims 69 to 84, wherein one hundred or more doses of the composition are administered.

89. The method of any one of claims 69 to 88, wherein the dose of composition is administered at least once per week.

90. The method of any one of claims 69 to 88, wherein the dose is administered at least twice weekly.

91. The method of any one of claims 69 to 88, wherein the dose is administered at least three times per week.

92. The method of any one of claims 69 to 88, wherein the dose is administered at least once daily.

93. The method of any one of claims 69 to 88, wherein the dose is administered at least twice daily.

94. The method of any one of claims 69-93, wherein the dose is administered for at least 7 days.

95. The method of any one of claims 69-93, wherein the dose is administered for at least 30 days.

96. The method of any one of claims 69-93, wherein the dose is administered for at least 60 days.

97. The method of any one of claims 69-93, wherein the dose is administered for at least 90 days.

98. The method of any one of claims 1-97, wherein the composition is formulated as a pill, tablet, or capsule.

99. The method of any one of claims 1-98, wherein the composition is administered orally.

100. The method of any one of claims 1 to 99, wherein the composition is self-administered.

101. The method of any one of claims 1-100, wherein the subject is a human.

102. A method according to one of claims 1-101, further comprising the step of obtaining a sample from the subject.