AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: Preliminary Six Month Safety Results of an Ongoing Phase I/II Gene Therapy Trial

Abstract

Purpose : To assess preliminary safety data of the investigational subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human REP-1-encoding cDNA in choroideremia (CHM).

Methods : Nine subjects with CHM (ages 26-57 years), received uniocular subfoveal injections of low dose (up to 5x10¹⁰ vector genome (vg) per eye, n=5) or high dose (up to 1x10¹¹ vg per eye, n=4) AAV2-hCHM. Patients were evaluated pre- and post-operatively for 6 months with follow-up ongoing. Ocular safety was assessed by ophthalmic examination, perimetry, spectral domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-FAF).

Results : There were no surgery-related complications or unexpected adverse events. Visual acuity (VA) returned to baseline in all but one patient who slowly recovered to within 20 letters of baseline by 6 months. This subject had foveal thinning (to ~80% of baseline) and foveal sensitivity loss. All other patients showed no obvious changes in foveal structure post-injection. Mean sensitivity by light-adapted perimetry (10-2 protocol) was unchanged in treated and control eyes. Fundus perimetry showed non-significant (<3SD of the intervisit variability) increases in light sensitivity in some locations and subjects in the operated eye. Cone-mediated sensitivities by two-color dark-adapted perimetry showed non-significant increases in sensitivity above mean baseline for some locations in the operated eye of three subjects. Residual islands of retinal pigment epithelium preservation by SW-FAF showed trace reduction in area that was not significantly different in the injected eye compared to the control. There were no obvious dose-dependent relationships.

Conclusions : VA returned to baseline in most subjects after subfoveal injections of AAV2-hCHM. Foveal thinning and slow recovery of VA with unchanged perifoveal function in one patient raises the possibility of non-vector related individual vulnerability to the subfoveal injection. Not unexpectedly, short-term increases in sensitivity in the operated eyes of a subset of patients did not exceed the intervisit or inter-ocular variability estimates. Longer observation intervals are required to better evaluate the significance of the preliminary changes.

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