A gene-augmentation framework for selected early-stage autosomal recessive retinitis pigmentosa genotypes

Many recessive inherited retinal dystrophies are, in principle, amenable to gene augmentation, yet only one such therapy has received regulatory approval. We sought to identify potentially tractable autosomal recessive retinitis pigmentosa (RP) genotypes that might be addressed using publicly described adeno-associated virus (AAV) components. More than 100 RP-associated genes were prioritized according to cellular expression, coding-sequence size, and the availability of cell type-directed promoters, yielding 19 candidate genes expressed predominantly in rods and/or retinal pigment epithelium (RPE). In rhesus monkey eyes, the human RHO and BEST1 promoters supported rod- and RPE-enriched expression, respectively, whereas the tested GFAP and RLBP1 constructs were limited by undetectable Müller glial expression or RPE abnormalities under the tested exposure conditions. We selected PDE6B as a proof-of-concept gene and evaluated AAV8-RHO-PDE6B after neonatal subretinal delivery. The vector preserved outer nuclear layer structure, electroretinographic responses, and visually guided behavior in rd1 and rd10 mice, with effects observed through 6 months. Higher tested doses were associated with retinal abnormalities, whereas fewer detectable abnormalities were observed at the lower doses through day 56 in rhesus monkey eyes. Together, these findings define a preclinical framework for developing gene-augmentation vectors for selected early-stage autosomal recessive RP genotypes.