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Glaucoma Is The Third Leading Cause Of Blindness Worldwide.
About 2% of people over age 40 will suffer glaucoma.
Glaucoma is a disorder characterized by optic nerve damage and progressive visual field loss associated to high intraocular pressure (IOP). Peripheral loss of vision is clinically evident when a significant number of the axons that comprise the optic nerve are lost, but glaucoma is otherwise indolent. Thus, the onset of high IOP is difficult to anticipate and often patients have been exposed to high IOP for an undetermined period of time, leading to some nerve damage and loss of vision. High IOP is a risk factor for glaucoma, which pharmacological therapy can normalize. Yet, in spite of successful IOP reduction, the disease remains chronic and many patients go on losing optic nerve (ON) fibers and continue to lose vision. In sum, open angle glaucoma is a slow, chronic, and progressive neuro-degenerative disease of RGC death. High IOP is an important factor in RGC death, but not always found. Thus, therapies that only normalize IOP often fail. Mimetogen Pharmaceuticals has considered two additional mechanisms:
neuroprotection of stressed RGCs and the discovery of molecular changes in the retina that are triggered by high IOP.
Neuroprotection
Mimetogen has developed highly selective and potent Trk agonists (e.g. MIM-D3) that prevent neuronal death. These agents have been tested in vivo in animal models of glaucoma and age-associated memory decline. These are disorders in which the affected neurons express the targeted TrkA receptor and are responsive to treatment with MIM-D3.
Novel Targets For Treatment Of Glaucoma.
While high IOP is clearly correlated with eventual RGC death in glaucoma, there are virtually no links made at the molecular level between high IOP and RGC death. There is a large “black box” bracketed by the onset of high IOP and the resulting chronic RGC death after an the unknown span of high IOP. What causes the selective death of RGCs? High IOP alone cannot account for selective RGC death. The mechanical pressure of high IOP affects all of the retina but only kills RGCs, which make up less than 5% of retinal cells. While neurons may be more sensitive to pressure, the fact that chronic RGC death continues after IOP normalization must have alternative explanations.
Mimetogen has worked to reduce the size of this large black box.
Traditional mechanisms proposed to explain RGC death in glaucoma include: (i) excitotoxic damage (hyperactive NMDA receptors, elevated glutamate, Ca++, and nitric oxide), (ii) ischemic or immune-mediated retinal injury leading to activation of microglia and macrophages and bystander damage of neighboring retinal cells, (iii) remodeling irregularities within the extracellular matrix diminishing its support for RGCs, and causing decreased blood flow to the head of the optic nerve, and (iv) mechanical compression of the optic nerve head preventing axonal transport (also known as “physiologic axotomy”).
These traditional mechanisms do not account for some key issues. First, they do not explain why only RGCs are susceptible to death despite exposure of all cells of the retina. Second, they do not explain why normalization of IOP does not completely arrest of RGC death, since all pathologies should revert to homeostasis. Third, all postulated mechanisms should lead to acute rather than chronic and progressive RGC death.
In order to address these issues, we studied gene expression in the retina, triggered by ocular hypertension for a certain time span. High IOP regulated genes may be “bullets” etiological to chronic RGC damage. After triggering these “bullets”, high IOP would no longer be absolutely required for chronic RGC death.
Four criteria defined the “trigger” hypothesis. First, any molecular changes triggered must be induced by high IOP, rather than arising as the result of RGC damage. Second, molecular changes must be triggered relatively early after the onset of high IOP. Third, molecular changes triggered must be sustained even after high IOP is normalized. Fourth, molecular changes must sensitize or prime RGCs for death.
We demonstrated that changes in gene expression selectively caused by high IOP, and meeting the above criteria lead to RGC death through several pathways never before documented for glaucoma: In one, genes that are normally required for RGC maintenance are down-regulated. In another, genes that are selectively neurotoxic are up-regulated.
Using this information, we developed novel therapeutic rationales.
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