Preclinical Evaluation of ADVM-062, a Novel Intravitreal Gene Therapy for the Treatment of Blue Cone Monochromacy

Abstract

Purpose : Blue cone monochromacy (BCM) is a debilitating, rare X-linked retinal disease resulting from the congenital absence of both L- and M-opsins, that causes severely impaired color discrimination, low vision, nystagmus, and photophobia. We developed ADVM-062, a vector optimized for intravitreal (IVT) delivery aimed at restoring the cone-specific expression of human L-opsin (hL-Opsin). This vector utilizes AAV.7m8 capsid that has been demonstrated to provide efficient transduction of foveal cones in primate retina when delivered intravitreally and uses the opsin LCR and a minimal M-opsin promoter to express human L-opsin in cones. The present study evaluated the dose dependent safety as well as levels and localization of hL-Opsin expression to establish the tolerability and potential efficacy of IVT-delivered ADVM-062 in nonhuman primates (NHPs).

Methods : Cynomolgus monkeys were treated with 5E9, 5E10, or 5E11 vg/eye ADVM-062 or vehicle via bilateral IVT injection, and monitored for ocular and systemic tolerability for 8wk without any steroid treatment. Retinal levels of hL-Opsin in the presence of endogenous NHP opsins were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at 8wk post-treatment. Retinal localization was evaluated by immunofluorescence (IF) analysis by using another AAV.7m8-based vector made to express myc-tagged hLOpsin IVT delivered at the same doses as ADVM-062. Transduction efficiency was determined as a percentage of hL-Opsin.myc–positive foveal cones in a series of histological retinal sections.

Results : IVT administration of ADVM-062 was well tolerated up to the highest dose of 5E11vg/eye and resulted in dose-dependent hL-Opsin expression. Cone specificity was confirmed by colocalization of cone cell markers in IF analyses of retinas expressing myc-tagged hL-opsin. ADVM-062 at lowest dose of 5E9 vg/eye resulted in variable transduction of foveal cones from 4.8% to 49.8%, and doses at 5E10 and 5E11 vg/eye resulted in transduction of foveal cones from 17.7% to 85.3% in the individual animals.

Conclusions : Based on published studies of minimal foveal cone density sufficient to maintain good visual acuity in humans with retinal degenerative diseases or dichromatic vision, our data suggest that IVT ADVM-062 at well tolerated doses may effectively transduce sufficient numbers of foveal cones to potentially achieve clinical efficacy.

This is a 2021 ARVO Annual Meeting abstract.