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

Abstract

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.