Gene Therapy Study for Monogenic Blindness Fails to Meet Endpoint


The researchers unexpectedly found sustained visual improvement in both eyes, despite only 1 eye being treated with AAV.

Patrick Yu-Wai-Man, PhD

A gene therapy involving adeno-associated viral (AAV) vectors for treating monogenic blinding diseases has failed to meet the primary endpoints of the study.

A team, led by Patrick Yu-Wai-Man, Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).

Leber hereditary optic neuropathy (LHON) is caused by mutations in mitochondrial DNA (mDNA), while a recombinant AAV, rAAV2/2-NDA has shown promise providing therapeutic effects in mouse models of LHON.

The Trial

The researchers conducted a randomized, double-masked, sham-controlled, multicenter. phase 3 clinical trial involving 37 individuals with LHON bearing a MT-ND4 mutation. Each participant’s right eye was randomly assigned in a 1:1 ratio for either rAAV2/2-ND4 (GS010) treatment or a sham injection. 

The investigators sought a primary endpoint of as the difference in the change in BCVA from baseline to week 48 between the 2 treatment groups.

The left eye of patients also received the treatment not allocated to the right eye.

Surprising Results

“Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period,” the authors wrote.

The researchers found at week 96, the eye received the gene therapy showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters).

They also found a mean improvement of -0.258 LogMAR (+13 letters) in the sham-treated eyes.

However, they did not meet the primary endpoint (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least 1 eye, while 29 participants (78%) had an improvement in vision in both eyes.

In addition, the investigators conducted a non-human primate trial to investigator the bilateral improvement found in the human trial. Here they found evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function following unilateral injection.

A Look Back at ASRS Data

A single-injection intravitreal gene therapy that can durably express an intraocular anti-VEGF agent could reduce the need for repeated anti-VEGF injections and improve outcomes for patients with neovascular age-related macular degeneration (nAMD).

A team, led by Charles C. Wykoff, MD, PhD, Director of Clinical Research, Retina Consultants of Houston, presented initial findings at the American Society of Retina Specialists (ASRS) 2020 Virtual Meeting on the safety and biological activity of a novel intravitreal anti-VEGF gene therapy in neovascular age-related macular degeneration.

As noted in the intermediate cohort, there were observed statistically significant differences in mean retinal sensitivity between the treated and untreated eyes (1.05 decibel [dB]; 90% CI, 0.81-1.29).

In both low and intermediate dosage cohorts, statistically significant differences were observed in central visual field progression rate between the treated and untreated eyes (low: 1.10 dB-sr/year; 90% CI, 0.10-2.10; intermediate: 1.26 dB-sr/year; 90% CI, 0.65-1.86).

The study, “Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy,” was published online in Science Translational Medicine.

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