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Byron L Lam, William J Feuer, Janet L Davis, Vittorio Porciatti, Hong Yu, Robert Levy, Elizabeth Vanner, John Guy; Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of all Patient Groups. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1576 – A0365.
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© ARVO (1962-2015); The Authors (2016-present)
Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease causing severe visual loss. We performed a phase 1 LHON G11778A gene therapy clinical trial (NCT02161380) to assess the safety and tolerability of AAV2(Y444,500,730F)-P1ND4v2 that utilizes allotopic expression.
The phase 1 open-label clinical trial was designed as a 3+3 dose escalation of unilateral intravitreal gene therapy injection for each group of G11778A LHON patients with visual loss. Setting: single institution. Participants: 28 adult patients (5 females) 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 (5.0 x 108 vg), medium (2.5 x 109 vg), high (2.4 x 109 vg), or higher (1.0 x 1010 vg) dose to worse eye (20/200 or worse) for Groups 1 and 2 and better eye (20/40 or better) for Group 3. Outcome Measures: Best-corrected visual acuity (BCVA), visual field, pattern electroretinogram. optical coherence tomography, adverse events, and vector antibody responses. BCVAs were compared to our published prospectively natural history cohort with designated surrogate study and fellow eyes. Longitudinal analysis was performed with generalized estimating equation analysis.
Incident uveitis (8/28,29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose, 5/7(71%) higher-dose eyes versus 3/21(14%) low-, medium-, or high-dose eyes (p<0.001). Incident uveitis was not associated with anterior chamber or serum AAV2 neutralizing antibody titers, or serum AAV2 PCR. Improvements of >15 letter BCVA occurred in both treated and fellow eyes of Groups 1 and 2 and 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 if there is an efficacy effect, it is likely small and not dose-related. Instances of substantial improvement of >15 ETDRS letters were not uncommon in our natural history patients suggesting demonstration of gene therapy efficacy in LHON likely requires randomization of patients to a group not receiving vector in either eye.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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