Targets for Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration, leading to vision loss. Understanding the molecular targets involved in RP is pivotal for elucidating disease mechanisms, identifying therapeutic interventions, and supporting drug development. Among the targets provided, only Rhodopsin (RHO) has a direct, well-established role in RP pathogenesis. Mutations in the RHO gene are the most common cause of autosomal dominant RP, accounting for approximately 25–30% of such cases. Rhodopsin is critical for phototransduction in rod photoreceptors, and its structural or functional defects lead to photoreceptor cell death via mechanisms such as protein misfolding, endoplasmic reticulum stress, and apoptosis. The study of RHO mutations has provided insight into disease progression, genotype-phenotype correlations, and has enabled the development of gene therapy and pharmacological chaperone strategies. Other targets listed (e.g., CLDN5, DHFR, FFAR4, NTRK1, NFE2L2, NOS2, PPARA, SIGMAR1) do not have direct, demonstrable roles in RP pathogenesis based on current evidence. Thus, a focused analysis on Rhodopsin (RHO) is essential for understanding RP mechanisms and therapeutic avenues.

Phototransduction And Photoreceptor Degeneration

This category encompasses molecular targets directly implicated in the phototransduction cascade and the degeneration of rod photoreceptors, which are central to the pathogenesis of retinitis pigmentosa. The only target in this category with a direct, well-established role in RP is Rhodopsin (RHO). Mutations in RHO disrupt the phototransduction process, leading to misfolded protein accumulation, photoreceptor cell stress, and apoptosis. This ultimately results in the progressive loss of vision characteristic of RP. The molecular mechanisms involve protein misfolding, endoplasmic reticulum stress, activation of the unfolded protein response, and apoptotic cell death. Rhodopsin (RHO) thus serves as both a mechanistic biomarker and a therapeutic target for RP, with gene therapy and pharmacological chaperones representing current intervention strategies.

Rhodopsin (RHO)

Rhodopsin (RHO) is a G protein-coupled receptor (GPCR) encoded by the RHO gene (Entrez: 6010, KEGG: 6010, UniProt: P08100) and is the principal photopigment in rod photoreceptors. Structurally, rhodopsin consists of seven transmembrane α-helices, a retinal-binding lysine residue (K296), and cytoplasmic and extracellular loops critical for G protein interaction and signal transduction. Rhodopsin is regulated by light-induced conformational changes and phosphorylation by rhodopsin kinase, followed by arrestin binding. Pathogenic mutations in RHO (over 150 identified) cause autosomal dominant retinitis pigmentosa (adRP) by mechanisms including protein misfolding (e.g., P23H, the most common North American mutation), impaired trafficking, and constitutive activation or inactivation. Misfolded rhodopsin accumulates in the endoplasmic reticulum, triggering the unfolded protein response (UPR), ER-associated degradation (ERAD), and apoptosis of rod photoreceptors. This cell death leads to secondary cone degeneration and progressive vision loss. The pathogenic role of RHO mutations is supported by animal models (e.g., P23H and S334ter mutant rats/mice) and human genetic studies. Therapeutically, RHO is a validated gene therapy target: adeno-associated virus (AAV)-mediated gene replacement and gene editing approaches are in preclinical and early clinical development. Pharmacological chaperones (e.g., 11-cis-retinal analogs) have shown efficacy in stabilizing misfolded RHO. RHO mutations also serve as genetic biomarkers for diagnosis and prognosis. The clinical significance of RHO is underscored by ongoing gene therapy trials (e.g., NCT04123626), making it a cornerstone of RP research and treatment.