Clinical progress in gene therapy for RPGR-associated X-linked retinitis pigmentosa

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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. Its equivalence to full-length RPGR in human photoreceptors remains uncertain. Trial design is equally important. 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. In XIRIUS, baseline microperimetry was repeated three times over two days to minimize learning effects. Disease-appropriate, reproducible and clinically meaningful endpoints are therefore essential for evaluating therapeutic benefit.