AAV8-hLCA5 Subretinal Delivery to the Macula in LCA5-associated Leber Congenital Amaurosis (LCA5-LCA): Preliminary Safety and Efficacy 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 8 (AAV8) vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-LCA.

Methods : This is a nonrandomized, single ascending, phase 1b/2a dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26 and 34 years old), received uniocular SR injections of up to 300 µl of a low dose [1x10¹⁰ vector genome (vg) per eye] of OPGx-001. Patients were evaluated pre- and post-operatively for up to three months with follow-up ongoing. Ocular safety, the primary endpoint, was assessed by ophthalmic examination and spectral domain optical coherence tomography (SD-OCT). Secondary endpoints of efficacy herein were visual acuity (VA), Full-field Stimulus Test (FST), and performance in a Virtual Reality Orientation and Mobility (VR-O&M) test.

Results : OPGx-001 was well tolerated to date with no surgery- or drug-related complications or unanticipated adverse events. VA returned to baseline or improved in the treated eye of all trial participants. SD-OCT showed no changes in thickness or retinal lamination of the treated central retina after treatment. In one of the patients, dark-adapted, cone-mediated sensitivities improved. This was confirmed objectively by dark-adapted chromatic pupillometry. Improvements in vision were also associated with better performance on the VR-O&M test. A second patient with rod-mediated vision by dark-adapted FSTs did not show FST improvements, and a third patient has not reached the one month FST readout date.

Conclusions : Administration of OPGx-001 by SR injection appears to be safe and well tolerated. There were subjective and objective signs of biologic efficacy even in these severely affected patients. Efficacy at lowest dose warrants careful dose escalation. Longer observation intervals are required to better evaluate the significance of the preliminary changes.

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