Home > Publications Database > Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy. > print

001     276827
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024 7 _ |a 10.1001/jamaophthalmol.2024.5375
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024 7 _ |a 2168-6173
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037 _ _ |a DZNE-2025-00340
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Yu-Wai-Man, Patrick
|b 0
245 _ _ |a Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.
260 _ _ |a Chicago, Ill.
|c 2025
|b American Medical Association
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
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650 _ 7 |a NADH dehydrogenase subunit 4
|2 NLM Chemicals
650 _ 7 |a NADH Dehydrogenase
|0 EC 1.6.99.3
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650 _ 7 |a DNA, Mitochondrial
|2 NLM Chemicals
650 _ 2 |a Optic Atrophy, Hereditary, Leber: genetics
|2 MeSH
650 _ 2 |a Optic Atrophy, Hereditary, Leber: therapy
|2 MeSH
650 _ 2 |a Optic Atrophy, Hereditary, Leber: physiopathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Genetic Therapy: methods
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Visual Acuity: physiology
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Follow-Up Studies
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Prospective Studies
|2 MeSH
650 _ 2 |a Treatment Outcome
|2 MeSH
650 _ 2 |a NADH Dehydrogenase: genetics
|2 MeSH
650 _ 2 |a Genetic Vectors
|2 MeSH
650 _ 2 |a Young Adult
|2 MeSH
650 _ 2 |a Dependovirus: genetics
|2 MeSH
650 _ 2 |a Adolescent
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a DNA, Mitochondrial: genetics
|2 MeSH
650 _ 2 |a Quality of Life
|2 MeSH
700 1 _ |a Newman, Nancy J
|b 1
700 1 _ |a Biousse, Valérie
|b 2
700 1 _ |a Carelli, Valerio
|b 3
700 1 _ |a Moster, Mark L
|b 4
700 1 _ |a Vignal-Clermont, Catherine
|b 5
700 1 _ |a Klopstock, Thomas
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700 1 _ |a Sadun, Alfredo A
|b 7
700 1 _ |a Sergott, Robert C
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700 1 _ |a Hage, Rabih
|b 9
700 1 _ |a Degli Esposti, Simona
|b 10
700 1 _ |a La Morgia, Chiara
|b 11
700 1 _ |a Priglinger, Claudia
|b 12
700 1 _ |a Karanja, Rustum
|b 13
700 1 _ |a Taiel, Magali
|b 14
700 1 _ |a Sahel, José-Alain
|b 15
700 1 _ |a Group, LHON Study
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|e Collaboration Author
700 1 _ |a Barboni, Piero
|b 17
|e Contributor
700 1 _ |a Carbonelli, Michele
|b 18
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700 1 _ |a Di Vito, Lidia
|b 19
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700 1 _ |a Amore, Giulia
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700 1 _ |a Contin, Manuela
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700 1 _ |a Mohamed, Susan
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700 1 _ |a Silvestri, Sara
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700 1 _ |a Hendrick, Andrew M
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700 1 _ |a Dattilo, Michael
|b 26
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700 1 _ |a Peragallo, Jason H
|b 27
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700 1 _ |a Hawy, Eman
|b 28
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700 1 _ |a DuBois, Lindreth
|b 29
|e Contributor
700 1 _ |a Gibbs, Deborah
|b 30
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700 1 _ |a Fernandes Filho, Alcides
|b 31
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700 1 _ |a Dobbs, Jannah
|b 32
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700 1 _ |a Aung, Andre
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700 1 _ |a Acheson, James
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700 1 _ |a Boston, Hayley
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700 1 _ |a Eleftheriadou, Maria
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700 1 _ |a Gemenetzi, Maria
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700 1 _ |a Leitch-Devlin, Lauren
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700 1 _ |a Tucker, William R
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700 1 _ |a Jurkute, Neringa
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700 1 _ |a Burale, Asma
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700 1 _ |a DeBusk, Adam A
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700 1 _ |a Haller, Julia A
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700 1 _ |a Massini, Maria
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700 1 _ |a SantaMaria, Melissa
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700 1 _ |a Tollis, Heather
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700 1 _ |a Girmens, Jean-François
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700 1 _ |a Plaine, Lise
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700 1 _ |a Khemliche, Wahiba
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700 1 _ |a Catarino, Claudia B
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700 1 _ |a Priglinger, Siegfried
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700 1 _ |a Rudolph, Günther
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700 1 _ |a Thurau, Stephan
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700 1 _ |a von Livonius, Bettina
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700 1 _ |a Muth, Daniel
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700 1 _ |a Al-Tamami, Jasmina
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700 1 _ |a Schertler, Cosima
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700 1 _ |a Hildebrandt, Martin
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700 1 _ |a Neuenhahn, Michael
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700 1 _ |a Heilweil, Gad
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700 1 _ |a Tsui, Irena
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773 _ _ |a 10.1001/jamaophthalmol.2024.5375
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