• Gene Therapy for LHON

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

    Journal Highlights

    Ophthalmology, May 2021

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    Newman et al. evaluated gene therapy as an early intervention for Leber hereditary optic neuropathy (LHON). The primary efficacy end point was not achieved, with equivalent improvement in visual acuity (VA) observed in both treatment and control eyes.

    For this phase 3 trial, the researchers enrolled patients with the m.11778G>A mitochondrial DNA muta­tion who experienced vision loss within six months of LHON onset. The right eye of each patient was assigned randomly to receive one in­jection of rAAV2/2-ND4 (9 × 1010 viral genomes in 90 μL) or one sham injection. The left eye was given the other treatment. The prima­ry end point was a clinically significant difference (–0.3 logMAR; 15 letters) in BCVA from baseline to week 48. Follow-up continued to week 96.

    The efficacy analysis included 38 patients (mean age, 36.8 years; 82% male). The mean duration of vision loss at treatment was 3.6 months (active) and 3.9 months (sham). Mean base­line logMAR BCVA (standard devia­tion [SD]) was 1.31 SD and 1.26 SD, respectively. At week 48, the difference in BCVA change from baseline between active and sham treatments was –0.01 logMAR (p = .89). Initially, mean BCVA declined in both groups, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then improvement of 10 and 9 ETDRS letters, respectively, from the plateau level to week 96. At final follow-up, vision outcomes were comparable for both groups of eyes. Treatment was well tolerated.

    Although the primary end point of this study was not met, bilateral im­provement of VA occurred, which has been observed but is inconsistent with the typical natural history of visual outcomes of LHON. These findings have implications for the design of future neuro-ophthalmologic trials of gene therapy, said the authors. (Also see related commentary by John J. Chen, MD, PhD, in the same issue.)

    The original article can be found here.