A multinational study, RESTORE, has demonstrated that lenadogene nolparvovec, a gene therapy for Leber hereditary optic neuropathy (LHON) due to the MT-ND4 gene variant, provides sustained improvement in visual acuity up to 5 years post-treatment. The findings, published in JAMA Ophthalmology, suggest a lasting therapeutic benefit for this rare inherited disease that leads to severe vision loss.
The RESTORE study followed 62 patients from the original RESCUE and REVERSE trials, where patients received a single intravitreal injection of lenadogene nolparvovec in one eye and a sham injection in the other. The study aimed to assess the long-term efficacy and safety of the gene therapy.
Sustained Visual Acuity Improvement
After 5 years, patients showed a mean change in best-corrected visual acuity (BCVA) of -0.4 logMAR (more than +4 lines) in treated eyes and -0.4 logMAR (+4 lines) in sham eyes (difference -0.05, 95% CI -0.15 to 0.04, P =0.27). This bilateral improvement was unexpected, suggesting a potential transfer of the vector DNA to the contralateral eye, as hypothesized by researchers. According to José-Alain Sahel, MD, PhD, of the Centre Hospitalier National D'Ophtalmologie des Quinze Vingts in Paris, the vision improvement is "likely to be a lasting effect."
Clinical Recovery and Quality of Life
Clinically relevant recovery, defined as a BCVA improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least one eye, was observed in 66.1% of participants (41 of 62). Furthermore, patients reported improvements in quality of life, with significant gains in seven of 10 NEI VFQ-25 subscales, including mental health and role difficulties, and a composite score increase of seven points.
Safety and Tolerability
The gene therapy demonstrated a favorable long-term safety profile. While some patients experienced mild ocular adverse events such as cataracts, intraocular inflammation, and elevated intraocular pressure, no permanent complications were reported. Intraocular inflammation occurred in 16.7% of treated eyes between years two and five, a decrease from 79.0% during the first two years.
Expert Commentary
In an accompanying commentary, Hendrik Scholl, MD, of Medical University of Vienna, and Bence György, MD, PhD, of the University of Basel in Switzerland, noted that the initial results of the RESCUE and REVERSE trials were "somewhat puzzling" because they did not meet their primary outcomes. They suggested that the analysis based on changes from nadir might be misleading and recommended tracking BCVA changes from baseline.
Future Directions
Despite the promising results, further studies are needed to confirm these findings and to explore the therapy's impact on younger populations. According to Sahel, a confirmatory study will likely be required for approval in the U.S. and some European countries. The company plans further studies, and he expects approval in the U.S. to come in 3 to 4 years.
Lenadogene nolparvovec, developed by GenSight Biologics, represents a significant advancement in the treatment of LHON, offering a potential long-term solution for patients with this debilitating condition. However, the cost of the therapy, estimated at $725,000 per patient for bilateral treatment in 2021, remains a significant barrier to access.
