Purpose: To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). Design: Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. Participants: Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. Methods: Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. Main Outcome Measure: Loss of visual acuity. Results: For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P < 0.001). Two patients demonstrated asymptomatic uveitis that resolved without treatment. Optical coherence tomography of treated eyes showed an average temporal retinal nerve fiber layer thickness of 54 μm before injection and 55 μm at month 12. For fellow eyes before injection, it was 56 μm, decreasing to 50 μm at month 12 (P = 0.013). Generalized estimating equations suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by approximately 0.05 μV (P = 0.009 exchangeable). No difference between eyes in outcomes of other visual function measures was evident. Conclusions: Allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer, opening the door next for testing of the high dose.
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