Progress in gene therapy for RPGR-associated X-linked retinitis pigmentosa

X-linked retinitis pigmentosa (XLRP) caused by pathogenic variants in RPGR is among the most severe inherited retinal dystrophies, with childhood-onset nyctalopia followed by progressive visual-field constriction and central visual loss. The purine-rich ORF15 terminal exon has driven sustained development of adeno-associated virus-mediated gene supplementation.

This review summarizes the molecular biology of RPGR, the challenge of stabilizing the ORF15 transgene, the principal clinical programs, and endpoint selection in pivotal trials.

Clinical development has followed two transgene strategies: codon optimization preserving full-length RPGR^ORF15, or a construct containing a 126-amino-acid deletion removing approximately 36% of the Glu-Gly-rich region and 6 of 11 identified glutamylation consensus motifs. Beyond transgene design, appropriate endpoint selection is critical to demonstrating therapeutic efficacy in RPGR-XLRP. The multi-luminance mobility test was developed for RPE65-associated retinal dystrophy, where visual-cycle restoration can rapidly improve night vision, and may be less suited to slowly progressive RPGR-XLRP. Microperimetry can detect localized changes in retinal sensitivity but requires careful standardization and repeated baseline testing to minimize learning effects. Low-luminance visual acuity (LLVA) represents an attractive primary functional endpoint for: it is simple, standardized and clinically meaningful, while challenging central visual function under conditions in which RPGR-XLRP patients may be impaired despite preserved conventional acuity. Importantly, XIRIUS demonstrated treatment-related improvements in LLVA and mean microperimetry sensitivity, supporting the responsiveness of both measures to therapeutic intervention in RPGR-XLRP. LLVA and microperimetry are well suited to primary efficacy assessment in RPGR-XLRP, with endpoint selection guided by disease stage and the anticipated treatment effect and supported by complementary structural biomarkers.