Targeting Neogenin as a Novel Therapeutic Approach for the Treatment of Retinal Degeneration

Retinitis Pigmentosa (RP) is a genetically inherited condition characterized by progressive loss of photoreceptor cells and represents one of the most prevalent causes of blindness among working age populations. The mechanisms leading to photoreceptor death remain largely unknown and there are no available treatments. We have previously shown that the protein Neogenin is involved in regulating cell survival in the CNS. Here we show that Neogenin expression is induced in degenerating photoreceptors in two mouse RP models (Rd1 and Rd10). Degenerating photoreceptors have abnormally high levels of cGMP and cAMP, and here we demonstrate that 8-Bromo-cAMP administration was sufficient to induce Neogenin expression in-vivo in wild type mouse photoreceptors and in-vitro in human photoreceptor surrogate cells. Using targeted in-vivo electroporation, we then demonstrate that i) overexpressing Neogenin in mouse photoreceptors induces cell death and ii) that silencing Neogenin in degenerating Rd1 photoreceptors promotes survival. This suggests Neogenin acts as a previously unidentified pro-death signal in RP. To develop a potential therapeutic approach for targeting Neogenin in RP, we utilized a Neogenin function blocking peptide (4Ig) we developed that is capable of blocking Neogenin’s pro-apoptotic activity. Intravitreal injections of 4Ig were administered at the onset of photoreceptor degeneration in Rd1 and Rd10 mice. When assessed at advanced stages of disease progression, 4Ig treatment significantly improved rod photoreceptor survival and cone photoreceptor survival. Photoreceptor function was also significantly improved following 4Ig treatment as demonstrated by i) improved light-evoked ganglion cell recordings, ii) improved scotopic/photopic electroretinogram recordings and iii) improved visual acuity (OptoMotry; CerebralMechanics). Targeting Neogenin therefore represents an exciting new approach for the treatment of RP.Ph.D.2020-07-10 00:00:0