• Gene Therapy for Leber Hereditary Optic Neuropathy

    Written By: Lynda Seminara
    Selected By: Stephen D. McLeod, MD

    Journal Highlights

    Ophthalmology, November 2017

    Download PDF

    Guy et al. expanded their research on gene therapy for Leber hereditary optic neuropathy (LHON) and found that their collective results affirm the benefits of low and moderate doses.

    In this open-label trial, 9 patients with visual loss and mutated G11778A mitochondrial DNA received a unilateral single-dose intravitreal injection of corrected DNA borne by the adenoassociated vector AAV2(Y444,500,730F)-P1ND4v2, which had also been administered previously to 5 other patients. Six of the 14 patients had bilateral visual loss lasting > 12 months (group 1), 6 had bilateral loss for < 12 months (group 2), and 2 had unilateral loss (group 3).

    Eight patients received the low dose (5 × e9 vg), and 6 received the medium dose (2.46 × e10 vg). Nine patients had follow-up for ≥ 12 months.

    Testing included visual acuity (VA), visual field, optical coherence tomography, and pattern electroretinography (PERG). Generalized estimating equations were used in longitudinal analyses. The main outcome was change in VA.

    Because the study was not randomized or controlled, results were compared with data from the authors’ previous natural history cohort, with inclusion limited to those who would have qualified for the gene therapy at baseline. The worse eye of natural history patients served as a surrogate for treated eyes in the current study; better eyes served as fellow eyes.

    For groups 1 and 2 combined, the average improvement over 12 months was 0.24 logMAR in treated eyes and 0.09 logMAR in fellow eyes. The difference in improvement between study and fellow eyes was greater in group 2 than in the natural history cohort at month 12 (0.53 vs. 0.21 logMAR; p = .053) and month 18 (0.96 vs. 0.17 logMAR; p < .001).

    The average thickness of the temporal retinal nerve fiber layer (RNFL) was 54 μm before injection and 55 μm at month 12. The respective values for fellow eyes were 56 μm and 50 μm. Estimating-equation analysis showed that PERG amplitudes worsened more in treated eyes. No between-eye differences were detected by other visual function measures. Two patients exhibited uveitis, which was asymptomatic and resolved.

    In conclusion, low and medium doses of allotopic gene therapy appear safe for treating LHON and do not damage the temporal RNFL. These findings warrant testing of higher doses.

    The original article can be found here.