Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups

• Published in: American journal of ophthalmology Vol. 241; pp. 262 - 271
• Main Authors: Lam, Byron L., Feuer, William J., Davis, Janet L., Porciatti, Vittorio, Yu, Hong, Levy, Robert B., Vanner, Elizabeth, Guy, John
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2022; Elsevier Limited
• Subjects: Adenosine triphosphatase; COVID-19; Dependovirus - genetics; Dependovirus - metabolism; Diabetic retinopathy; DNA, Mitochondrial - genetics; Drug dosages; Electroretinography; FDA approval; Gene therapy; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic Vectors; Humans; Mitochondrial DNA; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Natural history; Optic Atrophy, Hereditary, Leber - genetics; Optic Atrophy, Hereditary, Leber - therapy; Patients; Prospective Studies; Retinal Ganglion Cells; Tomography, Optical Coherence; Vision Disorders - etiology; Visual Acuity; Visual Fields
• ISSN: 0002-9394; 1879-1891; 1879-1891
• DOI: 10.1016/j.ajo.2022.02.023

To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). Phase 1 clinical trial. Setting: single institution. Participants: Patients with G11778A LHON and chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8). Intervention: unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Outcome Measures: Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes. Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P < .001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment. G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye.