Bilateral Visual Improvement with Unilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON)

Abstract

Purpose : To assess the clinical efficacy of a single intravitreal injection of rAAV2/2-ND4 (GS010), an investigational gene therapy for Leber hereditary optic neuropathy (LHON) caused by the m.11778G>A mitochondrial DNA (mtDNA) mutation. LHON is a mitochondrial inherited disease that preferentially targets retinal ganglion cells causing severe bilateral visual loss. The m.11778G>A mtDNA mutation in the MTND4 gene accounts for 75% of all LHON cases. rAAV2/2-ND4 is a gene therapy enabling allotopic expression and delivery of the wild-type ND4 protein to mitochondria of retinal ganglion cells.

Methods : RESCUE (NCT02652767) and REVERSE (NCT02652780) are Phase III, randomized, double-masked, sham-controlled trials in which LHON subjects with the m.11778G>A mutation received a single unilateral intravitreal injection of rAAV2/2-ND4. Visual function, retinal anatomy and quality-of-life measures were monitored for 96 weeks following administration. A concurrent study on 3 non-human primates with an equivalent unilateral injection was performed.

Results : In REVERSE subjects, rAAV2/2-ND4-treated eyes gained on average +15 ETDRS letters at Week 96 compared with baseline. Sham-treated eyes showed an improvement of +13 ETDRS letters, counter to the expected natural history of the disease. In RESCUE subjects, mean best-corrected visual acuity (BCVA) worsened to a nadir in both eyes, followed by a bilateral improvement from Week 48 to Week 96. On average, rAAV2/2-ND4-treated eyes in RESCUE gained +26 ETDRS letters at Week 96 compared with their nadir BCVA.
A clinically relevant response (CRR) from the nadir was observed in at least one eye of 78% of REVERSE subjects and 63% of RESCUE subjects. In comparison, a natural history study reported that only 28% of LHON subjects with the m.11778G>A mutation had a spontaneous CRR from the nadir in at least one eye.
The presence of viral vector DNA in the fellow uninjected eye was demonstrated in the non-human primates.

Conclusions : Final results of RESCUE and REVERSE showed clinically meaningful improvements of visual function. The transfer of rAAV2/2 ND4 to the sham-treated eye could explain the unexpected improvement in the contralateral eye.

This is a 2020 ARVO Annual Meeting abstract.