Treatment Potential of RPGRIP1-associated Inherited Retinal Degenerations

Abstract

Purpose : To determine the treatment potential in Leber congenital amaurosis (LCA) resulting from RPGRIP1 (retinitis pigmentosa GTPase regulating–interacting protein 1) mutations.

Methods : Thirteen patients, six pediatric (ages 1-17 years) and seven adults (24 - 68 years), from 11 families with RPGRIP1-LCA underwent complete ophthalmic examination. Imaging was performed with spectral domain optical coherence tomography (SD-OCT) and, in a subset of patients, en-face imaging with fundus autofluorescence and wide angle color photography. Visual function was measured with full-field electroretinography (ERGs), full-field sensitivity test (FST), and two-color dark-adapted perimetry. Not all patients had all tests.

Results : Visual acuity (VA) in the better seeing eye ranged from light perception (LP) to 20/125 in pediatric patients, from 20/250 to LP in the adult patients. Earliest abnormalities in pediatric patients were in the pericentral to midperipheral retina. Although photoreceptor loss was already present in the youngest patient at a year of age, all patients with SD-OCT (including our oldest) showed retained photoreceptors within the central retina. Outer nuclear layer (ONL) thickness was within or near normal limits in most patients near the fovea but decreased rapidly with increasing eccentricity and was often barely detectable or undetectable outside of the eccentricity of the vascular arcades. Retained central ONL with detectable signals at inner/outer segment interface was associated with severely abnormal cone-mediated function. Rod-mediated function was not detectable except in three young patients (ages 7, 10 and 17) who showed at least a log unit of rod sensitivity loss. Photoreceptor loss in blind retina was associated with signs of inner retinal remodeling.

Conclusions : RPGRIP1-LCA patients showed retained central photoreceptors across a large life-span and showed structural-functional dissociation, which is an ideal scenario for gene augmentation treatments.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.