학술논문
Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.
Document Type
Academic Journal
Author
Newman NJ; Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia. Electronic address: ophtnjn@emory.edu.; Yu-Wai-Man P; Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.; Carelli V; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy; Unit of Neurology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; Moster ML; Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania.; Biousse V; Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia.; Vignal-Clermont C; Department of Neuro-Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France.; Sergott RC; Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania.; Klopstock T; Department of Neurology, Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Sadun AA; Doheny Eye Institute/UCLA School of Medicine, Los Angeles, California.; Barboni P; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.; DeBusk AA; Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania.; Girmens JF; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France.; Rudolph G; Department of Ophthalmology, University Hospital, LMU Munich, Munich, Germany.; Karanjia R; Doheny Eye Institute/UCLA School of Medicine, Los Angeles, California; Department of Ophthalmology, University of Ottawa Eye, Ottawa, Ontario, Canada.; Taiel M; GenSight Biologics, Paris, France.; Blouin L; GenSight Biologics, Paris, France.; Smits G; GenSight Biologics, New York, New York.; Katz B; GenSight Biologics, New York, New York.; Sahel JA; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; Fondation Ophtalmologique A. de Rothschild, Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; CHNO des Quinze-Vingts, Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC, Paris, France.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 7802443 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-4713 (Electronic) Linking ISSN: 01616420 NLM ISO Abbreviation: Ophthalmology Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).
Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.
Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.
Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.
Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.
Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.
Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
(Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)
Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.
Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.
Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 10
Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.
Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.
Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
(Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)