neurology today

Intraocular gene therapy for Leber’s hereditary optic neuropathy (LHON) appears safe and therapeutically promising, according to new research presented at the annual meeting.

But an unexpected improvement in the untreated eye of patients who received a unilateral injection means researchers will likely need another trial before the therapy is ready for Food and Drug Administration (FDA) approval. the United States.

LHON is a rapidly progressive, blinding disease caused by a mutation in the mitochondrial gene, most commonly in the ND4 gene, which is part of the Complex I energy-producing machinery. Previous gene replacement studies have shown that a unilateral injection in one eye, accompanied by a sham procedure without injection in the other, leads to improvements in both the injected eye and the non-injected eye, more than one would have expected. expect relative to natural history. The data.

“What was surprising in these studies was that the uninjected eye also improved, and more than we expected over the course of natural history,” said project leader Nancy. J. Newman, MD, FAAN, professor of ophthalmology and neurology at Emory University. Follow-up work in monkeys indicated that the gene vector appears to have “somehow traveled to the opposing eye and optic nerve, resulting in measurable improvement”.

This good news came too late to influence the design of the current trial, said Dr Newman, who again injected a gene therapy vector into one eye, but this time injected into the second eye either therapy gene (n=48) or placebo (n=50); no patient received any treatment.

The researchers evaluated the participants 18 months after the injection. As before, treatment was safe, with only mild to moderate intraocular inflammation that could be treated with topical medication. And as before, eyes that received gene therapy improved – in this trial, by 19 letters on the standard ETDRS eye chart for the first eye, and 16 letters in the second eye for those receiving bilateral injection. Placebo-treated eyes improved by 13 letters, all compared to the nadir of post-treatment vision.

“This was more than predicted by natural history,” Dr. Newman said, and since patients who received therapy in both eyes did better in the second eye than those who received a placebo, “this suggests that there was indeed some sort of dose effect.”

The benefit of even bilateral treatment was “modest”, Dr Newman said, “but it’s a good first step”. Nonetheless, she said, a new trial will be required. “It wasn’t a case-control study by person, but by eye, and we now know that was a mistake on our part – we don’t have naive controls, and that’s something that we hope to do in the future,” she explained. .

“It’s exciting to have a treatment that can improve vision in this devastating disease, especially if the treatment improves both eyes,” said John Chen, MD, PhD, associate professor of ophthalmology and neurology at Mayo. Clinic in Rochester, MN, which was The magnitude of improvement observed in this trial from the nadir of vision loss “is likely to be clinically significant, but it is important to note that the final visual outcome was worse than baseline vision. Therefore, a future clinical trial with randomization of patients in a group not receiving gene therapy in either eye will be needed to confirm the efficacy of this promising treatment.”

The study was sponsored by GenSight Biologics.

Drs. Newman and Chen had no relevant disclosures.

Abstract AAN P17.002: Newman N, Yu-Wai-Man P, Carelli V, et al. The Phase III REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for Leber’s Hereditary Optic Neuropathy (LHON).​