Am J Ophthalmol. 2023 Sep 14:S0002-9394(23)00362-8. doi: 10.1016/j.ajo.2023.09.005. Online ahead of print.
PURPOSE: To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON).
DESIGN: Phase 1 clinical trial.
METHODS: 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), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Mean follow-up was 33.6 months (range 18-36).
RESULTS: Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of Group 3 and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes with some eyes having modest improvement that may be related to natural history or gene therapy. Mean NEI-VFQ-25 scores declined in Group 3 subjects (p=0.023), CONCLUSIONS: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCLIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history.