Genetic Therapies for Retinitis Pigmentosa: Current Breakthroughs and Future Directions

Retinitis pigmentosa is a group of inherited retinal dystrophies characterized by progressive photoreceptor cell loss leading to irreversible vision loss. Affecting approximately 1 in 4000 individuals worldwide, retinitis pigmentosa exhibits significant genetic heterogeneity, with mutations in genes such as RHO, PRPF31, RPE65, USH2A, and NR2E3, which contribute to its diverse clinical presentation. This review outlines the genetic basis of retinitis pigmentosa and explores cutting-edge gene-based therapeutic strategies. Luxturna (voretigene neparvovec-rzyl), the first FDA-approved gene therapy targeting RPE65 mutations, represents a milestone in precision ophthalmology, while OCU400 is a gene-independent therapy that uses a modified NR2E3 construct to modulate retinal homeostasis across different RP genotypes. Additionally, CRISPR-Cas genome-editing technologies offer future potential for the personalized correction of specific mutations, though concerns about off-target effects and delivery challenges remain. The article also highlights MCO-010, a novel optogenetic therapy that bypasses defective phototransduction pathways, showing promise for patients regardless of their genetic profile. Moreover, QR-1123, a mutation-specific antisense oligonucleotide targeting the P23H variant in the RHO gene, is under clinical investigation for autosomal dominant RP and has shown encouraging preclinical results in reducing toxic protein accumulation and preserving photoreceptors. SPVN06, another promising candidate, is a mutation-agnostic gene therapy delivering RdCVF and RdCVFL via AAV to support cone viability and delay degeneration, currently being evaluated in a multicenter Phase I/II trial for patients with various rod-cone dystrophies. Collectively, these advances illustrate the transition from symptom management toward targeted, mutation-specific therapies, marking a major advancement in the treatment of RP and inherited retinal diseases.