glaucoma is essentially a fluid blockage in the eye, caused by a physical obstruction. Fluid is produced faster than it can escape, causing a pressure build up which eventually wreaks havoc on the optic nerve. I am not sure how one would reverse that with our type of therapy.
As explained in the PYC patent Methods of Treating Glaucoma
Glaucoma can be triggered when the aqueous humour builds up in the front part of the eye. Excess production or reduced draining of the aqueous humour increases the intraocular pressure (IOP), which irreversible damages the optic nerve and RGCs (retinal ganglion cells)….
In all subtypes of glaucoma, the gradual loss of RGCs is the hallmark. RGC dysfunction and death lead to vision impairment and ultimately blindness…. (1)
To date, reduction in IOP has been the only therapeutic approach to reduce the progression of glaucoma, but this approach has its limitations. In approximately one third of glaucoma cases, the condition develops despite normal IOP levels in the eye. Additionally, patients can deteriorate at all IOP levels and despite receiving IOP-lowering therapy. In one clinical study, over 40% of glaucoma patients progressed after 7 years and in another study, 60% showed statistically significant deterioration after an average of 8 years (1,2).
It is now widely accepted that glaucoma is a multifactorial disease, that various molecular pathways are implicated in the degeneration process and that novel therapeutic approaches are needed. There is growing interest in neuroprotection as an alternative therapeutic approach (3). PYC’s proposed therapeutic strategy for glaucoma comes under this umbrella.
As further explained in the PYC patent
…there is an urgent need to identify therapeutic strategies for RGC neuroprotection to limit the projected burden of vision impairment and blindness from glaucoma. The use of neurotrophic factors such as brain derived-, ciliary derived-, glial cell derived, and nerve growth factor has been a focus of recent research for it is known to prevent uncontrolled RGCs loss and aid to the cell viability. However, their effectiveness is limited by a relatively short half-life, insufficient permeability, and poor concentrations in target RGCs…. (1)
In the PYC patent it is proposed that an antisense oligonucleotide be used to increase functional OPA1 protein levels in order to promote RGC survival and thereby treat, prevent and/or delay progression of glaucoma.
A growing body of research has implicated mitochondrial dysfunction in glaucomatous degeneration. Mitochondrial dysfunction increases the susceptibility of RGCs to stress from risk factors such as elevated IOP, light exposure and vascular insufficiency (4).
There is preclinical evidence that supports the hypothesis that increased OPA 1 might protect against RGC loss in glaucoma.
A 2010 study by US researchers in a mouse model of glaucoma found that increased OPA 1 expression protected against RGC death.
These results demonstrate a direct relationship between OPA1 expression in RGCs and RGC survival, as well as support the possibility that increased OPA1 expression may promote RGC survival in glaucoma. Thus, direct enhancement of OPA1 may provide a new strategy to protect RGC death in various optic neuropathies including glaucoma (4).
A 2018 mouse model study by Chinese researchers investigated whether increased expression of OPA1 can protect RGCs and the mechanisms involved.
….our findings demonstrate that overexpression of OPA1 protects RGCs by ways of enhancing mitochondria fusion and parkin mediated mitophagy in experimental glaucoma. Interventions to promote mitochondrial fusion and mitophagy may provide a useful strategy to battle against glaucomatous RGC loss (5).
PYC’s own preclinical research in patient derived models of Autosomal Dominant Optic Atrophy (ADOA) highlights how OPA1 can protect RGCs from cell death (6). Rohan Hockings has indicated that PYC-001 (due to commence testing in ADOA human trials mid-year) could also be tested for efficacy in other bioenergetic diseases of the RGCs.
With multiple factors contributing to the disease and multiple subtypes, glaucoma is a higher risk indication than the monogenic haploinsufficiency diseases that PYC is currently chasing. Further, with over 80 million people affected worldwide, glaucoma is a blockbuster indication that would require a level of resources that small biotechs like PYC simply don’t have.
But if the PYC-001 in ADOA program yields promising safety and efficacy data, a much larger pharma might be keen to investigate PYC’s proposed approach to treat glaucoma.
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