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Published on: July 5, 2022
Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE
Valérie Biousse1, Nancy J Newman, Patrick Yu-Wai-Man
1Departments of Ophthalmology (VB, NJN), Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia; Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit (PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit (PY-W-M), Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital (PY-W-M, SE), London, United Kingdom; UCL Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom; IRCCS Istituto delle Scienze Neurologiche di Bologna (VC, CLM), Programma di Neurogenetica, Bologna, Italy; Unit of Neurology (VC, CLM), Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; Departments of Neurology and Ophthalmology (MLM, RCS), Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Neuro Ophthalmology and Emergencies (CV-C), Rothschild Foundation Hospital, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts (CV-C, RH, J-AS), Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France ; Department of Neurology (TK), Friedrich-Baur-Institute, University Hospital, LMU Munich, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (TK), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy) (TK), Munich, Germany; Doheny Eye Institute/UCLA School of Medicine (AAS, RK), Los Angeles, California; Department of Ophthalmology (CP), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany ; Department of Ophthalmology (RK), University of Ottawa Eye, Ottawa ON, Canada ; GenSight Biologics (LB, MT), Paris, France ; Sorbonne Université (J-AS), INSERM, CNRS, Institut de la Vision, Paris, France ; Fondation Ophtalmologique A. de Rothschild (J-AS), Paris, France; and Department of Ophthalmology (J-AS), the University of Pittsburgh School of Medicine, Pittsburgh.
Background:
RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials.
Methods:
In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25).
Results:
The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline.
Conclusion:
The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.
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