Inherited Retinal Disorders and their impact on vision loss
Inherited retinal diseases (IRDs) are a category of diseases that can cause significant vision loss leading to complete blindness. IRD occurs in families where one or more genes that control retinal cell structure and function are impaired. If a gene is altered, the corresponding protein may become abnormalor not produced at alleventually resulting in vision loss. There are over 270 different genes known to cause IRDs and many of which are degenerative. The most prevalent types of IRDs include: Retinitis Pigmentosa (RP), Stargardt Disease(SD), and Leber Congenital Amaurosis(LCA) among others. IRDs are typically unavoidable and progressive with limited therapeutic options. Since retina is small and easy to access for treatments compared to other regions, IRDs are ideal candidates for gene therapy. The most common strategy for gene therapy in the eye is to deliver the functional/corrected copy gene to the diseased retina using a vector, that. is a modified virus and does not multiply or cause structural damage. This would enable retinal cells to produce the normal protein leading to rescue of visual function.
AAV mediated gene augmentation
LCA is an autosomal recessive form of retinitis pigmentosa that appears in infancy/early childhood causing significant vision loss and eventually leading to complete blindness by adulthood. LCA13 is caused by a mutation in the RDH12 gene in photoreceptors, which aids in visual cycle. SD is the most common inherited macular dystrophy caused by an aberration in ABCA4 gene with an incidence of 1 in 8000–10,000 people. It is characterized by bilateral central visual loss with macular atrophy. At Eyestem, peripheral blood mononuclear cells (PBMCs) from LCA and SD patients were reprogrammed to Induced Pluripotent Stem Cells (iPSC) using episomal plasmids encoding Yamanaka factors – OCT4, SOX2, C-MYC, and KLF4. Currently, our primary focus is on gene therapy for LCA13, by delivering a copy of RDH12 gene using AAV based strategies. Preliminary in vitro experiments on AAV2/AAV5 mediated RDH12 augmentation in iPSC derived photoreceptor progenitors indicate promising results, and the preclinical studies are currently underway.
