Gene Therapy Shows Long-Term Vision Benefits in Rare Eye Disease

Patients with Leber hereditary optic neuropathy (LHON) due to the MT-ND4 gene variant treated with the gene therapy lenadogene nolparvovec in one eye showed a sustained improvement in best-corrected visual acuity (BCVA) in both eyes up to 5 years after treatment, the long-term RESTORE study showed.

Among 55 patients who completed the 5-year follow-up, bilateral vision improvement was similar to what was observed at the 2-year mark, with a mean change in BCVA of -0.4 logMAR (more than +4 lines) for treated eyes and -0.4 logMAR (+4 lines) for eyes treated with sham (difference -0.05, 95% CI -0.15 to 0.04, P=0.27), reported Patrick Yu-Wai-Man, MD, PhD, of the University of Cambridge in England, and colleagues.

In addition, an improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least one eye was observed in 66.1% of patients, they noted in JAMA Ophthalmology.

The findings suggest that vision improvement “is likely to be a lasting effect,” co-author José-Alain Sahel, MD, PhD, of the Centre Hospitalier National D’Ophtalmologie des Quinze Vingts in Paris, told MedPage Today. However, Sahel — a co-founder of the company that makes the gene therapy — said it may still take several years to get the treatment approved in the U.S.

LHON is a rare inherited disease that damages the optic nerve, and is estimated to affect one in 50,000 people. According to Sahel, patients with the condition have normal vision early in life but typically develop problems as teenagers or young adults. One eye and then the other loses vision, he said, and most patients become legally blind.

Sahel explained that lenadogene nolparvovec, an adeno-associated virus (AAV)-based ocular gene therapy, was designed to correct the genetic defect that causes LHON.

The initial RESCUE and REVERSE trials, patients from which comprise RESTORE, showed that vision in treated eyes improved at 2 years, but, unexpectedly, so did vision in untreated(sham) eyes, said Sahel, who noted that about 60% to 70% of patients were able to regain some level of vision.

“Most of them didn’t regain full vision, but several of them regained a good level of autonomy and the ability to read at least large print or medium print,” he added. Some patients were able to drive again, take part in sports, and go back to college.

This follow-up study showed that vision benefits persisted over 3 years beyond the initial studies, Sahel concluded, noting that no patients had permanent complications from the gene therapy, and inflammation occurring in some patients was manageable.

In an accompanying commentary, Hendrik Scholl, MD, of Medical University of Vienna, and Bence György, MD, PhD, of the University of Basel in Switzerland, said that the initial results of the RESCUE and REVERSE trials were “somewhat puzzling.”

The studies didn’t meet their primary outcomes — a difference in visual acuity between treated and untreated eyes — since vision in both eyes improved, they wrote. “One possibility [for this] is that the vector is trafficking from one eye to the other.”

Another possibility is the analysis may be misleading because the authors chose to track visual changes from nadir, which “may represent a 1-time event due to poor effort or poor fixation.”

The commentary authors recommended that “if investigators insist on using change from nadir, at a minimum, they should require 2 consecutive visits that confirm the stability of this nadir visit and, more importantly and primarily, consider BCVA changes from baseline.”

The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE) was conducted from 2018 to 2022 and tracked 62 of the 76 patients with LHON due to the MT-ND4 gene variant who took part in the initial two trials; 55 patients completed the 5-year follow-up. Mean age at treatment was 35.9, and 79% were men.

The mean baseline BCVA was 1.5 logMAR in the lenadogene nolparvovec group and 1.4 logMAR in sham eyes; after 2 years, the mean changes were -0.05 logMAR (+1 line) and 0.01 logMAR (-0 line), respectively (difference -0.03, 95% CI -0.16 to 0.09, P=0.60).

Over the 3-year follow-up period, intraocular inflammation occurred in four patients with eight events in eyes treated with lenadogene nolparvovec and one event in an eye treated with sham.

Sahel acknowledged that the gene therapy is likely to be expensive. In 2021, its manufacturer said the bilateral treatment would cost $725,000 per patient.

What’s next? “Most likely in the U.S. and in some countries in Europe, there will be a need for a confirmatory study to be performed,” he said, in light of the unusual initial results that didn’t allow comparison of treated and untreated eyes.

The company plans further studies, he added, and he expects approval in the U.S. to come in 3 to 4 years.