RPGR-related retinal dystrophy

Research into the natural history of the RPGR-associated retinal dystrophies such as retinitis pigmentosa (RP) and cone and cone-rod dystrophies (COD/CORD), can provide useful information in selecting candidates and determining clinical endpoints in gene therapy trials for the conditions, said Camiel Boon MD, PhD, FEBO, from Leiden University Medical Centre, and Amsterdam University Medical Centers, the Netherlands. “It may still seem far away but gene therapy is coming to our clinics and that is why it is important to discuss the genes that are eligible for gene therapy treatment,” Dr Boon told the 18th EURETINA Congress in Vienna, Austria. He noted that mutations in the RPGR gene are the most common cause of x-linked retinitis pigmentosa, accounting for 45-to-90% of cases. The largest proportion gene’s pathological variants are in its ORF 15 region. Some of the mutations are in exon 1 to 14 and also, though rarely, in exon 16 to 19. In trials involving the dog model and mouse model of RPGR-related retinal dystrophies, gene therapy appears to have provided improvements in vision. Three phase I trials looking at safety and possible efficacy are now under way. Prof Boon and associates conducted a retrospective study examining the clinical spectrum of the disease, the long-term outcome and to determine any genotype-phenotype correlations with clinical outcomes. The researchers reviewed the records of 74 patients from 38 families. The diagnosis was retinitis pigmentosa in 52 patients, CORD in 17 and COD in five. They had a median follow-up of 11.6 years (range 0.0-57.1) and median visits: 5 (range 3-55). Their analysis showed that the onset of symptoms occurred at mean age of five years in the retinitis pigmentosa group and at a mean age of 23 years in the COD/CORD groups. The main first symptom was night blindness in the retinitis pigmentosa group, and loss of visual acuity in the COD/CORD group. The probability of being blind at the age of 40 was 20% in patients with RP and 55% and COD/CORD, respectively. Two key findings were that high myopia was associated with a faster best-corrected vision decline in patients with RP (p<0.001) and COD/CORD (p=0.03) and that RPGR-ORF 15 mutations were associated with high myopia (p=0.01). In addition, the RP patients with ORF 15 mutations had a faster visual field decline (p=0.01) and a thinner central retina (p=0.03) than patients with mutations in exon 1 to 14. “The implications for gene therapy are that in an RPGR-associated retinitis pigmentosa there is essentially a wide intervention window, but in the cone and cone-rod dystrophies the window of opportunity might be narrower,” Prof Boon concluded. Camiel Boon: C.J.F.Boon@lumc.nl

Tags: cone-rod dystrophy, gene therapy, retinal dystrophy, retinitis pigmentosa