The visual pathway is a component of the central nervous system (CNS) and therefore is not regenerative. Acute optic nerve injury, ischemic optic neuropathy and glaucoma are conditions that initially lead to partial blindness and eventually could lead to total blindness. Extensive neuron and retinal ganglion cells (RGC) death is evidenced in these pathologies. Semaphorin 3A (Sema3A) is a cell secreted protein that participates in the axonal guidance pathways. Partner TAU was the first to show that Sema-3A is also capable of inducing neuronal cell death. Elevated levels of Sema3A were than found in glaucoma. TAU further showed the viscous role of Sema3a that is mediating the vast RCG apoptosis following optic nerve injury. Importantly, marked inhibition of RGC loss was achieved when axotomized eyes were co-treated by intravitreous injection of antibodies against the Sema3A providing the proof of concept for the therapeutic approach to inhibit the Sema3A pathway following optic nerve injury. This concept was recently validated by partner SIC who developed a small molecule weight inhibitor of Sema3A and showed that this inhibitor promotes neural regeneration of damaged axons. Acute or chronic assault to neural cells create an immediate death of part of the population and a signal for further death of the remaining cells close to the damaged area. The project goal is to develop a therapeutic approach to stop further death of neural cells by providing prolonged inhibition of the apopototic pathway of Sema-3A using antibody targeted to this protein or a low MW inhibitor of sema3A. The Sema3A inhibitors would be constantly released from a novel intraocular biodegradable implant. The clinical efficacy of this approach will be evaluated in two common devastating pathologies: optic nerve injury and glaucoma.
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