Gene Therapy Promising in Leber Hereditary Optic Neuropathy

Laird Harrison

November 13, 2021

A new gene therapy can significantly improve the visual acuity of people with Leber hereditary optic neuropathy (LHON), researchers say.

LHON often causes legal blindness, but in a compassionate use study, patients' best corrected visual acuity (BCVA) improved from an average of 2.0 (± 1.1) logMAR (counting fingers Snellen) to 0.9 (± .7) logMAR (20/160 Snellen) in the worst eye a year after treatment.

If the treatment is working as well as it appears from this and other studies, the achievement will be pathbreaking, said Gino Cortopassi, PhD, a professor of molecular biosciences at the University of California, Davis, who specializes in mitochondrial disorders and was not involved in the study.

"It's huge," he told Medscape Medical News, "because basically it hasn't happened before. It would be big news in gene therapy."

Surprisingly, the treatment improves vision not only in treated eyes, but also in untreated fellow eyes, a development with ramifications for other ocular gene therapies, according to Magali Taiel, MD, chief medical officer of GenSight Biologics, which is developing the treatment.

The results in the compassionate use study, presented here at the American Academy of Ophthalmology (AAO) 2021 annual meeting, parallels those in phase 3 clinical trials of the treatment, Taiel told Medscape Medical News. "A year and a half after treatment the improvement is massive," she said.

A rare maternally inherited genetic disease, LHON causes degeneration of retinal ganglion cells. It typically strikes in adolescence or early adulthood and affects men more often than women. It leads to sudden loss of central vision and usually involves both eyes within a year.

In the United States and the European Union about 800-1200 people lose their sight every year because of LHON. There is no approved treatment in the United States. Idebenone (Raxone) received marketing authorization in the European Union under exceptional circumstances, but it is not very effective, Taiel said.

The disease stems from an NADH dehydrogenase 4 (ND4) mutation that affects the ganglion cells' mitochondria. The therapy, lenadogene nolparvovec (Lumevoq), consists of an adeno-associated virus that replaces the defective gene.

The compassionate use study analyzed results in four children who were too young to meet the criteria for phase 3 trials and two adults who sought treatment after the phase 3 trials' enrollment closed.

At baseline, the patients' best corrected visual acuity ranged from hand motion at 24 cm to 41 Early Treatment Diabetic Retinopathy Study (ETDRS) letters.

One year after single injections in both eyes, the average best corrected visual acuity (BCVA) in the better eye improved from 1.45 (± .6) LogMar (20/640 Snellen) to 0.7 (± .3) LogMar (20/100 Snellen).

One patient, a 13 year old, improved bilaterally from hand motion to 55 ETDRS letters in one eye and 75 in the other.

The researchers also documented improvements in Pelli-Robson contrast sensitivity after 6 months. None of the patients experienced any adverse events beyond mild intraocular inflammation that resolved within 2 weeks, and there was no change in macular thickness measured on optical coherence tomography after 6 months.

BCVA was measured in only three patients at 1 year. While the small sample size and lack of a control made the study's statistics unimpressive, the findings paralleled those from its phase 3 clinical trials, most recently the REFLECT trial that GenSight described in a press release.

For REFLECT, researchers recruited 98 patients with vision loss due to LHON from centers in France, Spain, Italy, the United Kingdom, the United States, and Taiwan.

They administered a single intravitreal injection of lenadogene nolparvovec in the first affected eye. They randomly assigned the fellow eyes of 48 patients to second intravitreal injections with lenadogene nolparvovec and the fellow eyes of 50 patients to a placebo.

To their surprise, they found that mean visual acuity improved in both eyes in both groups (Table 1). This included the eyes that received only the placebo injections.

Table 1. Improvement in Visual Acuity at 1.5 Years

Patients Mean improvement in first affected eye, LogMAR/ETDRS letters Mean improvement in second affected eye, LogMAR?ETDRS letters Patients' mean BCVA at 1.5 years, LogMAR n
Bilaterally treated .23/12 .15/8 1.35 48
Unilaterally treated* .15/8 .08/4 1.45 50
*Second affected eye untreated.
BCVA = best corrected visual acuity, ETDRS = Early Treatment Diabetic Retinopathy Study


The researchers theorized that DNA from the treatment travels from one eye to the other through nerve axons via the synaptic transfer mechanism.

The treatment could not fully restore patients' vision because damage to the ganglion cells had already occurred before treatment began, Taiel said.

The mean difference between BCVA at baseline and BCVA at 1.5 years was significant in the first affected eyes (P = .001).

But the difference in improvement between eyes treated with placebo injections and those treated with lenadogene nolparvovec was not significant (P = .608). This meant the trial failed in its primary endpoint, Taiel acknowledged.

"We know that the natural history of these patients is not favorable," she said. "Most of them will stay blind starting at an early age. So it's an improvement comparing to natural history."

The company is in conversation with the US Food and Drug Administration about whether the results meet the regulators' standard for efficacy.

The researchers wanted to provide some benefit to the patients in the control group. But if they had anticipated the transfer of lenadogene nolparvovec from one eye to another, they would have created a control group in which patients did not receive the treatment at all, Taiel said. It's an important consideration for future ocular gene therapy trials, she said.

The news could buoy a field beset with treatment failures and adverse events in recent clinical trials, Cortopassi said.

The transfer of lenadogene nolparvovec from one eye to another raises questions about where else the genes might end up. But Cortopassi said he is not concerned about systemic adverse events because the genes are likely confined to the eyes and brain by the blood-brain barrier and blood-retina barrier.

In the REFLECT trial, systemic effects did not emerge, Taiel said. No one discontinued treatment due to an adverse event. As in the compassionate use trial, the main adverse event was intraocular inflammation, which responded to conventional treatment.

Cortopassi has reported no relevant financial relationships. Taiel is an employee of GenSight Biologics, which sponsored the trial.

AAO 2021 Annual Meeting. Abstract PO014. Presented November 12, 2021.

Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at or follow him on Twitter: @LairdH

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