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000276827 1001_ $$aYu-Wai-Man, Patrick$$b0
000276827 245__ $$aFive-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.
000276827 260__ $$aChicago, Ill.$$bAmerican Medical Association$$c2025
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000276827 520__ $$aLimited 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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000276827 650_7 $$2NLM Chemicals$$aNADH dehydrogenase subunit 4
000276827 650_7 $$0EC 1.6.99.3$$2NLM Chemicals$$aNADH Dehydrogenase
000276827 650_7 $$2NLM Chemicals$$aDNA, Mitochondrial
000276827 650_2 $$2MeSH$$aOptic Atrophy, Hereditary, Leber: genetics
000276827 650_2 $$2MeSH$$aOptic Atrophy, Hereditary, Leber: therapy
000276827 650_2 $$2MeSH$$aOptic Atrophy, Hereditary, Leber: physiopathology
000276827 650_2 $$2MeSH$$aHumans
000276827 650_2 $$2MeSH$$aGenetic Therapy: methods
000276827 650_2 $$2MeSH$$aMale
000276827 650_2 $$2MeSH$$aVisual Acuity: physiology
000276827 650_2 $$2MeSH$$aFemale
000276827 650_2 $$2MeSH$$aFollow-Up Studies
000276827 650_2 $$2MeSH$$aAdult
000276827 650_2 $$2MeSH$$aProspective Studies
000276827 650_2 $$2MeSH$$aTreatment Outcome
000276827 650_2 $$2MeSH$$aNADH Dehydrogenase: genetics
000276827 650_2 $$2MeSH$$aGenetic Vectors
000276827 650_2 $$2MeSH$$aYoung Adult
000276827 650_2 $$2MeSH$$aDependovirus: genetics
000276827 650_2 $$2MeSH$$aAdolescent
000276827 650_2 $$2MeSH$$aMutation
000276827 650_2 $$2MeSH$$aMiddle Aged
000276827 650_2 $$2MeSH$$aDNA, Mitochondrial: genetics
000276827 650_2 $$2MeSH$$aQuality of Life
000276827 7001_ $$aNewman, Nancy J$$b1
000276827 7001_ $$aBiousse, Valérie$$b2
000276827 7001_ $$aCarelli, Valerio$$b3
000276827 7001_ $$aMoster, Mark L$$b4
000276827 7001_ $$aVignal-Clermont, Catherine$$b5
000276827 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b6$$udzne
000276827 7001_ $$aSadun, Alfredo A$$b7
000276827 7001_ $$aSergott, Robert C$$b8
000276827 7001_ $$aHage, Rabih$$b9
000276827 7001_ $$aDegli Esposti, Simona$$b10
000276827 7001_ $$aLa Morgia, Chiara$$b11
000276827 7001_ $$aPriglinger, Claudia$$b12
000276827 7001_ $$aKaranja, Rustum$$b13
000276827 7001_ $$aTaiel, Magali$$b14
000276827 7001_ $$aSahel, José-Alain$$b15
000276827 7001_ $$aGroup, LHON Study$$b16$$eCollaboration Author
000276827 7001_ $$aBarboni, Piero$$b17$$eContributor
000276827 7001_ $$aCarbonelli, Michele$$b18$$eContributor
000276827 7001_ $$aDi Vito, Lidia$$b19$$eContributor
000276827 7001_ $$aAmore, Giulia$$b20$$eContributor
000276827 7001_ $$aContin, Manuela$$b21$$eContributor
000276827 7001_ $$aMohamed, Susan$$b22$$eContributor
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000276827 7001_ $$aBaker Hubbard, George$$b24$$eContributor
000276827 7001_ $$aHendrick, Andrew M$$b25$$eContributor
000276827 7001_ $$aDattilo, Michael$$b26$$eContributor
000276827 7001_ $$aPeragallo, Jason H$$b27$$eContributor
000276827 7001_ $$aHawy, Eman$$b28$$eContributor
000276827 7001_ $$aDuBois, Lindreth$$b29$$eContributor
000276827 7001_ $$aGibbs, Deborah$$b30$$eContributor
000276827 7001_ $$aFernandes Filho, Alcides$$b31$$eContributor
000276827 7001_ $$aDobbs, Jannah$$b32$$eContributor
000276827 7001_ $$aAung, Andre$$b33$$eContributor
000276827 7001_ $$aAcheson, James$$b34$$eContributor
000276827 7001_ $$aBoston, Hayley$$b35$$eContributor
000276827 7001_ $$aEleftheriadou, Maria$$b36$$eContributor
000276827 7001_ $$0P:(DE-2719)9002025$$aGemenetzi, Maria$$b37$$eContributor
000276827 7001_ $$aLeitch-Devlin, Lauren$$b38$$eContributor
000276827 7001_ $$aTucker, William R$$b39$$eContributor
000276827 7001_ $$aJurkute, Neringa$$b40$$eContributor
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000276827 7001_ $$aTollis, Heather$$b46$$eContributor
000276827 7001_ $$aGirmens, Jean-François$$b47$$eContributor
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000276827 7001_ $$aWolf, Armin$$b56$$eContributor
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000276827 7001_ $$aHeilweil, Gad$$b62$$eContributor
000276827 7001_ $$aTsui, Irena$$b63$$eContributor
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