Nancy J Newman1, Patrick Yu-Wai-Man2, Valerio Carelli3, Mark L Moster4, Valerie Biousse5, Catherine Vignal-Clermont6, Robert C Sergott4, Thomas Klopstock7, Alfredo A Sadun8, Piero Barboni9, Adam A DeBusk4, Jean François Girmens10, Günther Rudolph11, Rustum Karanjia12, Magali Taiel13, Laure Blouin13, Gerard Smits14, Barrett Katz14, José-Alain Sahel15. 1. Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia. Electronic address: ophtnjn@emory.edu. 2. 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. 3. 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. 4. Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania. 5. Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia. 6. Department of Neuro-Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France. 7. 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. 8. Doheny Eye Institute/UCLA School of Medicine, Los Angeles, California. 9. IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy. 10. Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France. 11. Department of Ophthalmology, University Hospital, LMU Munich, Munich, Germany. 12. Doheny Eye Institute/UCLA School of Medicine, Los Angeles, California; Department of Ophthalmology, University of Ottawa Eye, Ottawa, Ontario, Canada. 13. GenSight Biologics, Paris, France. 14. GenSight Biologics, New York, New York. 15. 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.
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.
RCT Entities:
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.
Authors: Micol Falabella; Michal Minczuk; Michael G Hanna; Carlo Viscomi; Robert D S Pitceathly Journal: Nat Rev Neurol Date: 2022-10-18 Impact factor: 44.711
Authors: Nancy J Newman; Patrick Yu-Wai-Man; Valerio Carelli; Valerie Biousse; Mark L Moster; Catherine Vignal-Clermont; Robert C Sergott; Thomas Klopstock; Alfredo A Sadun; Jean-François Girmens; Chiara La Morgia; Adam A DeBusk; Neringa Jurkute; Claudia Priglinger; Rustum Karanjia; Constant Josse; Julie Salzmann; François Montestruc; Michel Roux; Magali Taiel; José-Alain Sahel Journal: Front Neurol Date: 2021-05-24 Impact factor: 4.003
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