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Barrett Katz, Anne Galy, Serge Fitoussi, Catherine Vignal Clermont, Jose A. Sahel, Catherine Cancian, Nitza Thomasson, Celine BOUQUET; Intravitreal injection of rAAV2/2-ND4 in LHON: absence of correlation between ocular inflammation and humoral or cellular immune responses to AAV2. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4531. doi: https://doi.org/.
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A first-in-man, open-label, dose-escalation, Phase I/II safety study of rAAV2/2-ND4 was performed in LHON-ND4 subjects (NCT02064569). rAAV2/2-ND4, a recombinant AAV2 vector delivering the human wt ND4 protein to mitochondria of retinal ganglion cells via allotopic expression, was developed to treat LHON caused by G11778 ND4 mutation in mtDNA. Ocular and immune responses following intravitreal (IVT) administration of rAAV2/2-ND4 were studied in patients.
Fifteen subjects received an IVT injection of rAAV2/2-ND4 in their worse-seeing eye. Three subjects were included in each dose-escalation cohort (9×109, 3×1010, 9×1010, 1.8×1011 vg/eye) and an extension cohort (9×1010 vg/eye). Ocular examinations and quantification of humoral immune response (neutralizing antibodies (NAbs) - luciferase cell-based assay) and cellular immune response (IFN-γ ELISPOT) to AAV2 were performed up to Week 96 following IVT injection.
Thirteen subjects experienced transient anterior chamber and/or vitreous inflammation. All events were mild, except for one subject (#01-018) with severe inflammation. 11 of 13 subjects were treated with topical steroids and 2 with oral steroids. All events resolved without sequalae.At baseline, 7 of 15 subjects had no NAbs in the serum, while 2 (#01-001, #01-018) were highly positive (titers >1:1,000). Aqueous humor sampled from the last 8 subjects was negative in all cases, regardless of their NAb serum status. Only 2 subjects (#01-005, #01-018) had preexisting cellular immunity.After injection, NAbs increased in 11 subjects at Week 2 (7 subjects with titers >1:1,000). NAb titers peaked at Weeks 4-8 and returned to baseline at Weeks 48-78. The cellular response increased post-injection in the 2 subjects positive at baseline, and returned to baseline at Weeks 78-96. There was no correlation between immune response and dose level, and nor with ocular inflammation except for one subject (#01-018).
rAAV2/2-ND4 was well tolerated, with mostly mild transient ocular inflammation that was treatment responsive. rAAV2/2-ND4 induced a transient typical anti-AAV2 immune response that did not correlate with clinical inflammation. Additional follow-up in ongoing Phase III trials (Rescue NCT02652767 and Reverse NCT02652780) and the upcoming bilateral Phase III trial (Reflect NCT03293524) will help extend these observations.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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