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@ARTICLE{YuWaiMan:276827,
      author       = {Yu-Wai-Man, Patrick and Newman, Nancy J and Biousse,
                      Valérie and Carelli, Valerio and Moster, Mark L and
                      Vignal-Clermont, Catherine and Klopstock, Thomas and Sadun,
                      Alfredo A and Sergott, Robert C and Hage, Rabih and Degli
                      Esposti, Simona and La Morgia, Chiara and Priglinger,
                      Claudia and Karanja, Rustum and Taiel, Magali and Sahel,
                      José-Alain},
      collaboration = {Group, LHON Study},
      othercontributors = {Barboni, Piero and Carbonelli, Michele and Di Vito, Lidia
                          and Amore, Giulia and Contin, Manuela and Mohamed, Susan and
                          Silvestri, Sara and Baker Hubbard, George and Hendrick,
                          Andrew M and Dattilo, Michael and Peragallo, Jason H and
                          Hawy, Eman and DuBois, Lindreth and Gibbs, Deborah and
                          Fernandes Filho, Alcides and Dobbs, Jannah and Aung, Andre
                          and Acheson, James and Boston, Hayley and Eleftheriadou,
                          Maria and Gemenetzi, Maria and Leitch-Devlin, Lauren and
                          Tucker, William R and Jurkute, Neringa and Burale, Asma and
                          DeBusk, Adam A and Haller, Julia A and Massini, Maria and
                          SantaMaria, Melissa and Tollis, Heather and Girmens,
                          Jean-François and Plaine, Lise and Khemliche, Wahiba and
                          Catarino, Claudia B and Priglinger, Siegfried and Rudolph,
                          Günther and Thurau, Stephan and von Livonius, Bettina and
                          Muth, Daniel and Wolf, Armin and Al-Tamami, Jasmina and
                          Pressler, Angelika and Schertler, Cosima and Hildebrandt,
                          Martin and Neuenhahn, Michael and Heilweil, Gad and Tsui,
                          Irena},
      title        = {{F}ive-{Y}ear {O}utcomes of {L}enadogene {N}olparvovec
                      {G}ene {T}herapy in {L}eber {H}ereditary {O}ptic
                      {N}europathy.},
      journal      = {JAMA ophthalmology},
      volume       = {143},
      number       = {2},
      issn         = {2168-6165},
      address      = {Chicago, Ill.},
      publisher    = {American Medical Association},
      reportid     = {DZNE-2025-00340},
      pages        = {99},
      year         = {2025},
      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.},
      keywords     = {Optic Atrophy, Hereditary, Leber: genetics / Optic Atrophy,
                      Hereditary, Leber: therapy / Optic Atrophy, Hereditary,
                      Leber: physiopathology / Humans / Genetic Therapy: methods /
                      Male / Visual Acuity: physiology / Female / Follow-Up
                      Studies / Adult / Prospective Studies / Treatment Outcome /
                      NADH Dehydrogenase: genetics / Genetic Vectors / Young Adult
                      / Dependovirus: genetics / Adolescent / Mutation / Middle
                      Aged / DNA, Mitochondrial: genetics / Quality of Life / NADH
                      dehydrogenase subunit 4 (NLM Chemicals) / NADH Dehydrogenase
                      (NLM Chemicals) / DNA, Mitochondrial (NLM Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39699886},
      pmc          = {pmc:PMC11843360},
      doi          = {10.1001/jamaophthalmol.2024.5375},
      url          = {https://pub.dzne.de/record/276827},
}