Document Type
Article
Publication Date
2-1-2025
Abstract
IMPORTANCE: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).
OBJECTIVE: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.
DESIGN, SETTING, AND PARTICIPANTS: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye.
INTERVENTION: Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.
MAIN OUTCOMES AND MEASURES: Measures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events.
RESULTS: Among the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was -0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (-0 line) in gene therapy-treated and sham eyes, respectively (difference, -0.03; 95% CI, -0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of -0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and -0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, -0.05; 95% CI, -0.15 to 0.04; P = .27). An improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham.
CONCLUSIONS AND RELEVANCE: In this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03406104.
Recommended Citation
Yu-Wai-Man, Patrick; Newman, Nancy; Biousse, Valérie; Carelli, Valerio; Moster, Mark; Vignal-Clermont, Catherine; Klopstock, Thomas; Sadun, Alfredo; Sergott, Robert C; Hage, Rabih; Degli Esposti, Simona; La Morgia, Chiara; Priglinger, Claudia; Karanja, Rustum; Taiel, Magali; and Sahel, José-Alain, "Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy" (2025). Department of Neurology Faculty Papers. Paper 357.
https://jdc.jefferson.edu/neurologyfp/357
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PubMed ID
39699886
Language
English
Included in
Eye Diseases Commons, Investigative Techniques Commons, Neurology Commons, Ophthalmology Commons, Therapeutics Commons
Comments
This article is the author's final published version in JAMA ophthalmology, Volume 143, Issue 2, 2025, 99-108.
The published version is available at 10.1001/jamaophthalmol.2024.5375
Copyright © 2024 Yu-Wai-Man P et al. JAMA Ophthalmology.