Mutation independent gene therapy (MInT) for photoreceptor rescue in retinal dystrophie

Retinal dystrophies(RD) are a major cause of blindness caused by mutations in more than 250 genes, estimated to affect more than a million individuals in India with no locally available treatments. Photoreceptor death is an irreversible event leading to blindness in all RDs irrespective of the causative mutation.

Even the rescue of the primary gene mutation in the retina is inadequate, with visual function diminishing after a few years, as noted in clinical trials for gene therapy of Leber Congenital Amaurosis type-2 (LCA2). This occurs due to unabated photoreceptor death, compromising efficiency of AAV.RPE-65 gene therapy.

Therefore, we propose to rescue degenerating photoreceptors by modulation of chaperones, anti-apoptotic proteins and/or neurotrophic factors to halt or significantly delay retinal degeneration.

For this mutation-independent gene therapy(MInT) approach, we selected a small heat shock protein- HSPB1, inhibitor of apoptotic protein- BIRC2 and a neurotrophic factor- NGF, representing three distinct cellular mechanisms of preventing photoreceptor loss. Optimized Adeno-associated viral vectors will be used to deliver these genes in retinal dystrophy model(LCA2).

We will evaluate long-term safety and efficacy either as stand-alone or combinatorial gene therapy with the candidate gene(AAV-RPE65) and develop cGMP grade vectors for future human gene therapy trials applicable to RDs.