Interocular Symmetry of Rod and Cone Topography in Human ORF15-RPGR-XLRP Disease Despite Large Intraretinal, Intrafamilial and Interfamilial Variation

Abstract

Purpose : An important aim for the treatment of inherited retinal degenerations (IRDs) is to arrest the progressive loss of photoreceptors. One of the common IRDs is X-linked retinitis pigmentosa (XLRP) caused by mutations in the ORF15 exon of RPGR. Preclinical gene therapy studies in RPGR-mutant dogs and mice have shown success in arresting progressive degeneration with intervention initiated at clinically-relevant disease stages already with substantial loss of photoreceptors. Clinical trials in patients will require not only knowledge of retinotopic distribution of remaining rods and cones to treat but also methods for the efficient evaluation of modifications to the natural history of disease.

Methods : There were 70 patients (ages 8–71 years) from 45 families with mutations in the ORF15 exon of the RPGR gene. Static threshold perimetry was used to quantify rod and cone function across the 168 deg width of visual field. Overall disease severity was defined as sum of sensitivity losses across the retina. At each retinal locus, relative involvement of photoreceptors was estimated from the difference of rod and cone sensitivity losses. Interocular symmetry was evaluated by limits of agreement analysis for repeated measures with linked replications.

Results : Severity of disease showed substantial intra- and inter-familial variation that did not correlate with genotype after controlling for age. There were major intraretinal differences of disease, and retinotopic distribution of rod and cone dysfunction showed variegated patterns that could be different between individuals. When considering the inferior hemi-field likely to be targeted by potential treatments, more than 50% of the patients had detectable rod as well as cone function within a large swath of infero-temporal field spanning 50 to 100 deg eccentric. There was interocular symmetry with retina-wide limits of agreement of ~8 dB. Point-by-point measures of interocular variation in the infero-temporal field averaged 6.6 dB for rod function and 4.7 dB for cone function.

Conclusions : Many patients with ORF15-RPGR-XLRP retain rod and cone function within the infero-temporal field. Perimetry-based outcome measures can and should take advantage of high interocular symmetry of function in this region to determine safety and efficacy of uniocular interventions such as early phases of gene therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.