Journal Article

DZNE-2025-00340

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.

Yu-Wai-Man, P. ; Newman, N. J. ; Biousse, V. ; Carelli, V. ; Moster, M. L. ; Vignal-Clermont, C. ; Klopstock, T.DZNE* ; Sadun, A. A. ; Sergott, R. C. ; Hage, R. ; Degli Esposti, S. ; La Morgia, C. ; Priglinger, C. ; Karanja, R. ; Taiel, M. ; Sahel, J.-A. ; Group, L. S. (Collaboration Author) ; Barboni, P. (Contributor) ; Carbonelli, M. (Contributor) ; Di Vito, L. (Contributor) ; Amore, G. (Contributor) ; Contin, M. (Contributor) ; Mohamed, S. (Contributor) ; Silvestri, S. (Contributor) ; Baker Hubbard, G. (Contributor) ; Hendrick, A. M. (Contributor) ; Dattilo, M. (Contributor) ; Peragallo, J. H. (Contributor) ; Hawy, E. (Contributor) ; DuBois, L. (Contributor) ; Gibbs, D. (Contributor) ; Fernandes Filho, A. (Contributor) ; Dobbs, J. (Contributor) ; Aung, A. (Contributor) ; Acheson, J. (Contributor) ; Boston, H. (Contributor) ; Eleftheriadou, M. (Contributor) ; Gemenetzi, M. (Contributor)Extern* ; Leitch-Devlin, L. (Contributor) ; Tucker, W. R. (Contributor) ; Jurkute, N. (Contributor) ; Burale, A. (Contributor) ; DeBusk, A. A. (Contributor) ; Haller, J. A. (Contributor) ; Massini, M. (Contributor) ; SantaMaria, M. (Contributor) ; Tollis, H. (Contributor) ; Girmens, J.-F. (Contributor) ; Plaine, L. (Contributor) ; Khemliche, W. (Contributor) ; Catarino, C. B. (Contributor) ; Priglinger, S. (Contributor) ; Rudolph, G. (Contributor) ; Thurau, S. (Contributor) ; von Livonius, B. (Contributor) ; Muth, D. (Contributor) ; Wolf, A. (Contributor) ; Al-Tamami, J. (Contributor) ; Pressler, A. (Contributor) ; Schertler, C. (Contributor) ; Hildebrandt, M. (Contributor) ; Neuenhahn, M. (Contributor) ; Heilweil, G. (Contributor) ; Tsui, I. (Contributor)

2025
American Medical Association Chicago, Ill.

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Please use a persistent id in citations: doi:10.1001/jamaophthalmol.2024.5375

Abstract: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).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.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.Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.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.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.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.ClinicalTrials.gov Identifier: NCT03406104.

Keyword(s): Optic Atrophy, Hereditary, Leber: genetics (MeSH) ; Optic Atrophy, Hereditary, Leber: therapy (MeSH) ; Optic Atrophy, Hereditary, Leber: physiopathology (MeSH) ; Humans (MeSH) ; Genetic Therapy: methods (MeSH) ; Male (MeSH) ; Visual Acuity: physiology (MeSH) ; Female (MeSH) ; Follow-Up Studies (MeSH) ; Adult (MeSH) ; Prospective Studies (MeSH) ; Treatment Outcome (MeSH) ; NADH Dehydrogenase: genetics (MeSH) ; Genetic Vectors (MeSH) ; Young Adult (MeSH) ; Dependovirus: genetics (MeSH) ; Adolescent (MeSH) ; Mutation (MeSH) ; Middle Aged (MeSH) ; DNA, Mitochondrial: genetics (MeSH) ; Quality of Life (MeSH) ; NADH dehydrogenase subunit 4 ; NADH Dehydrogenase ; DNA, Mitochondrial

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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