Gene-Independent Combination Therapy for Rod-Cone Dystrophy

Rod-cone dystrophies are inherited retinal diseases whose clinical course begin with the degeneration of rod photoreceptors and evolve with the progressive loss of cones that, in turn, leads to complete blindness. These diseases affect 1:2500 individuals worldwide with many underlying gene defects.

Although gene replacement therapy has been very successful in treating inherited retinal degenerations in the clinic, with one FDA approved product on the market and over 30 clinical trials, it is costly and time consuming to develop a gene replacement therapy for each mutation.

Moreover, gene replacement can only be helpful if the underlying mutation is known and recessive.Despite the genetic heterogeneity of these diseases as well as their inherent complexity, all rod-cone dystrophies converge on a common phenotype of rod cell loss, followed by cone cell degeneration first in the periphery and then in the fovea, leading to complete blindness.

A gene therapy approach aiming to counteract the symptoms of rod-cone dystrophy rather than the individual genetic causes has the potential to be helpful in the highest number of affected patients.In this action we propose to develop a combination gene therapy to restore light sensitivity in mouse models of rod-cone dystrophies.

AAV-mediated expression of optogenetic channels in cone photoreceptors will restore light sensitivity and maintain downstream retinal circuitry processing.

The optogenetic therapy will be combined with the AAV-mediated delivery of rod derived cone viability factor (RdCVF), a factor normally secreted by rods to promote cone survival, lost in rod-cone dystrophies; RdCVF expression in combination with optogenetic channel expression will promote survival of newly lightsensitive cones.

Furthermore, this action proposes to deliver optogenetic channels and RdCVF to human retinal organoids, showing expression and photoreceptor activation in human tissue in vitro.