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John Guy, William J Feuer, Janet L Davis, Vittorio Porciatti, Rajeshwari D Koilkonda, Huijun Yuan, Byron L Lam, William Hauswirth; LHON Gene Therapy Clinical Trial: Year 2 Results. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5086.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the safety and tolerability of AAV2(Y444,500,730F)-P1ND4v2 in patients with LHON.
After obtaining informed consent for participation in this open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per subject in a dose-escalation study designed to investigate the safety of three vector doses (5x109 vg, 2.46x1010 vg or 1x1011 vg) in subjects with molecularly confirmed G11778A-mutated mitochondrial DNA; six patients with long-standing (>12 months) and bilateral acuity loss down to ≤ 35 ETDRS letters (20/200) received intravitreal injections of low dose study drug (5x109 vg) (n=3) or medium dose (2.46x1010 vg) (n=3) into the eye with worse acuity. Three patients with acute (<12 months) and bilateral acuity loss down to ≤ 35 ETDRS letters (20/200) received intravitreal injections of low dose study drug (5x109 vg) (n=3) into the eye with worse acuity. Clinical testing included ETDRS visual acuity, Humphrey visual fields (30-2), OCT, pattern ERG (perg) and neuro-ophthalmic examinations. Blood samples were screened for viral DNA and neutralizing antibodies (Nabs) to AAV2 prior and after intravitreal injection. Postinjection evaluations thus far are 1 year to 2 months.
None of the patients lost vision in the injected eyes. Adverse events were minor, but included low grade trace cell and flare anterior uveitis that was asymptomatic (n=2) and seen 2 months after injection resolving without intervention. Of these 2 patients, serum neutralizing antibodies with a titer of 1:80 preinjection rose to 1:20,480 7 days and 3 months postinjection. The other had a titer of 1:20,480 preinjection that remained unchanged. Vector DNA were not detected by qPCR in serum samples. All 3 patients with visual loss for less than a year who received the low dose had improvements of vision in injected eyes by 3 lines on the ETDRS chart. Of the 6 patients with chronic visual loss only 1 experienced improvement by 3 lines.
Study drug was associated with mild and transient anterior uveitis in 2 of 9 patients. Four of 9 (44%) patients experienced improvements in visual acuity with injection of Study drug relative to 8 patients (18%) who had spontaneous improvement of 3 lines or more out of the 44 patients entered into our prior natural history study (JAMA Ophthalmol. 2014:132(4):428-36). Thus far, study drug appears to be safe at low and medium doses.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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