阅读说明：本技术 青光眼的治疗 (Treatment of glaucoma ) 是由 L·布鲁斯 A·布鲁斯 于 2018-05-16 设计创作，主要内容包括：本发明的实施方案总体上涉及一种硫酸葡聚糖或其药学上可接受的盐,所述硫酸葡聚糖或其药学上可接受的盐用于治疗、抑制或预防受试者的青光眼。所述实施方案的硫酸葡聚糖实现眼内压的降低和标准化,这是在保存视网膜神经节细胞和视网膜神经纤维层方面的神经保护作用,并且所述硫酸葡聚糖溶解已建立的小梁网瘢痕元素。(Embodiments of the present invention generally relate to a dextran sulfate, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or preventing glaucoma in a subject. The dextran sulfate of the embodiments achieves a reduction and normalization of intraocular pressure, which is a neuroprotective effect in preserving retinal ganglion cells and the retinal nerve fiber layer, and dissolves established trabecular meshwork scar elements.)

1. A dextran sulfate, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or preventing glaucoma in a subject.

2. Dextran sulfate, or said pharmaceutically acceptable salt thereof, for use according to claim 1 for the treatment, inhibition or prevention of open angle glaucoma in said subject.

3. Dextran sulfate, or said pharmaceutically acceptable salt thereof, for use according to claim 2 for the treatment, inhibition or prevention of primary open angle glaucoma in said subject.

4. A dextran sulfate, or said pharmaceutically acceptable salt thereof, for use in reducing intraocular pressure in a subject suffering from glaucoma.

5. Dextran sulfate, or said pharmaceutically acceptable salt thereof, for use according to claim 4 for reducing intraocular pressure to within the normal intraocular pressure range of 10mmHg to 20 mmHg.

6. A dextran sulfate, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or preventing ocular hypertension in a subject.

7. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 6, wherein said subject has ocular hypertension caused by glaucoma.

8. A dextran sulfate, or a pharmaceutically acceptable salt thereof, for use in inhibiting retinal ganglion cell loss and retinal nerve fiber layer reduction in a subject suffering from glaucoma, preferably open angle glaucoma and/or ocular hypertension.

9. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 4, 5, 7, or 8, wherein said subject has open angle glaucoma.

10. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 9, wherein said subject has primary open angle glaucoma.

11. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof is formulated for systemic administration to said subject.

12. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 11, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof is formulated for intravenous or subcutaneous administration to said subject, preferably formulated for subcutaneous administration to said subject.

13. Dextran sulphate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein said dextran sulphate or said pharmaceutically acceptable salt thereof has an average molecular weight equal to or lower than 10000 Da.

14. Dextran sulphate or said pharmaceutically acceptable salt thereof for use according to claim 16, wherein said average molecular weight is in the range of 2000Da to 10000 Da, preferably in the range of 3000 Da to 10000 Da, and more preferably in the range of 3500Da to 9500 Da.

15. Dextran sulphate or said pharmaceutically acceptable salt thereof for use according to claim 14, wherein said average molecular weight is in the range of 4500 Da to 7500 Da, preferably in the range of 4500 Da to 5500 Da.

16. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 15, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof has an average sulfur content in the range of 15% to 20%.

17. The dextran sulfate, or said pharmaceutically acceptable salt thereof, for use according to claim 16, wherein said dextran sulfate, or said pharmaceutically acceptable salt thereof, has an average sulfur content of about 17%.

18. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein said dextran sulfate orThe pharmaceutically acceptable salt thereof has a number average molecular weight (M) as measured by Nuclear Magnetic Resonance (NMR) spectroscopy in the interval 1850Da to 3500Da, preferably in the interval 1850Da to 2500Da, and more preferably in the interval 1850Da to 2300Da_n)。

19. Dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 18, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof has an M within the interval of 1850Da to 2000Da as measured by NMR spectroscopy_n。

20. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to claim 18 or 19, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof has an average number of sulfate per glucose unit in the interval of 2.5 to 3.0, preferably in the interval of 2.5 to 2.8, and more preferably in the interval of 2.6 to 2.7.

21. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof has an average of 5.1 glucose units and an average number of sulfate per glucose unit of from 2.6 to 2.7.

22. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 21, wherein said dextran sulfate or said pharmaceutically acceptable salt thereof is formulated as an aqueous injection solution.

23. The dextran sulfate or said pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 22, wherein said pharmaceutically acceptable salt is a sodium salt of dextran sulfate.

Technical Field

Embodiments of the present invention relate generally to the prevention, treatment, or inhibition of glaucoma, and specifically to the use of dextran sulfate in the prevention, treatment, or inhibition of glaucoma.

Background

Glaucoma describes a group of progressive optic neuropathies that may cause irreversible blindness, with the main risk factor being elevated intraocular pressure (IOP). In Primary Open Angle Glaucoma (POAG), IOP elevation occurs when the outflow of aqueous humor (AqH) through the Trabecular Meshwork (TM) is reduced, usually as a result of abnormal TM cell structure, TM contraction, and extracellular matrix (ECM) levels. Elastic fibers in the TM are surrounded by a sheath of fine fibrils embedded in an amorphous ECM composed of collagen IV, laminin, and fibronectin. The presence of plaque material associated with the sheath of elastic-like fibers in the paracellular tissue (JCT) within the TM, the so-called sheath-derived (SD) plaque, is also a pathological feature of POAG. Thus, POAG patients had significantly more and thicker SD plaques in their TM compared to the eyes of age-matched controls. However, these SD plaques are not considered to contribute to increased outflow resistance in the industry because it has been shown that eyes with pseudoexfoliative glaucoma have similar SD plaque material levels when compared to healthy eyes, but still have higher IOP levels. However, increased ECM levels around the TM sheath were observed, and this deposition may contribute to increased outflow resistance. These cellular and ECM changes in the TM and altered TM cell contractile capacity lead to dysfunctional TM and ultimately to loss of tight control of AqH efflux.

The mechanism responsible for TM dysfunction in POAG may be multifactorial, but pathologically high levels of transforming growth factor-beta (TGF- β) within AqH are thought to contribute to the TM dysfunction. Some POAG patients have elevated TGF- β levels in AqH compared to AqH taken from age-matched patients with cataracts or other forms of glaucoma. The role of TGF- β in increasing TM ECM deposition and IOP has been demonstrated by human eye perfusion experiments and in rodent models of glaucoma. Gene expression studies from cultured human TM cells also support the following arguments: both TGF-beta 1 and TGF-beta 2 subtypes induce overexpression of ECM proteins that may contribute to the TM alterations observed in glaucoma. In addition, TGF- β inhibits the activation of Matrix Metalloproteinases (MMPs) by increasing the levels of Plasminogen Activator Inhibitor (PAI) -1 and Tissue Inhibitor of Metalloproteinases (TIMP), thereby preventing the decomposition of ECM. PAI-1 inhibits the conversion of plasminogen to plasmin required for plasmin-dependent MMP activation. The IOP-increasing effect of TGF-. beta.is also attributed to the ability of cytokines to reduce TM cell proliferation and induce TM cell apoptosis, thereby reducing the total number of TM cells.

TGF- β also stimulates contraction of TM cells via the RhoA-Rho associated protein kinase (ROCK) signaling pathway, where TM contractility significantly affects IOP. Studies using Rho/ROCK inhibitors to reduce or eliminate RhoA-mediated TM contraction have led to a new class of IOP lowering agents that are contemplated for use in the treatment of glaucoma and other medical conditions involving increased IOP. However, it is not possible to address the chronic fibrotic condition that occurs in some POAG patients with Rho/ROCK inhibitors alone, whose efficacy is still under review. Ultimately, elevated IOP leads to metabolic and biochemical changes in the cells of the optic nerve head and retina. In addition, mechanical axonal compression affects both retrograde and anterograde axonal transport. Metabolic and biochemical changes, together with mechanical axonal compression, deprive Retinal Ganglion Cells (RGCs) of neurotrophic factors, ultimately leading to RGC apoptosis and optic disc notching, which are diagnostic features of glaucoma.

Since the loss of vision from glaucoma is irreversible, the goal of any glaucoma treatment is to prevent vision loss. Glaucoma is currently treated by eye drops, pills, laser surgery, traditional surgery, or a combination of these methods. Most of these therapies are designed to reduce and/or control IOP, which may damage the optic nerve that conveys visual information to the brain. However, IOP control is also deficient at best and there remains an unmet need for improved therapies that can limit or even reverse disease progression.

Disclosure of Invention

The general goal is to treat, inhibit or prevent glaucoma in a subject.

This and other objects are achieved by embodiments as disclosed herein.

Drawings

The embodiments, together with further objects and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying drawings in which:

figure 1 illustrates changes in intraocular pressure (IOP) in subjects with Primary Open Angle Glaucoma (POAG) and treated with saline control or dextran sulfate according to embodiments.

Fig. 2 illustrates changes in Retinal Ganglion Cell (RGC) numbers in subjects with POAG and treated with saline control or dextran sulfate according to embodiments.

Fig. 3 illustrates changes in Retinal Nerve Fiber Layer (RNFL) thickness in subjects with POAG and treated with saline control or dextran sulfate according to an embodiment.

Fig. 4 illustrates anterior segment imaging of iridocorneal angle of subjects with POAG and treated with saline control or dextran sulfate according to embodiments.

Figure 5 illustrates changes in the laminin immunoreactivity of subjects with POAG and treated with a saline control or dextran sulfate according to an embodiment.

Fig. 6 illustrates the change in fibronectin immunoreactivity in the angle of the atria of subjects having POAG and treated with saline control or dextran sulfate according to the embodiments.

Figure 7 illustrates the body weight difference of subjects with POAG and treated with saline control or dextran sulfate according to an embodiment.

Fig. 8 is a representative fluorescein angiography image of a subject having POAG and treated with a saline control or dextran sulfate according to an embodiment.

FIG. 9 illustrates choroidal neovascularization stained with isolectin B4. Representative images of new blood vessel formation in the control group (fig. 9A) and the treatment group (fig. 9B). (FIG. 9C): the bar graph shows the average neovascular area.

FIG. 10 illustrates choroidal neovascularization using collagen type IV staining. Representative images of new blood vessel formation in the control group (fig. 10A) and the treatment group (fig. 10B). (FIG. 10C): the bar graph shows the average neovascular area.

FIG. 11 illustrates the results of Optical Coherence Tomography (OCT) analysis of RNFL.

One aspect of the embodiments relates to dextran sulfate, or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or preventing glaucoma in a subject.