LHON is a mitochondrial inherited disease that causes severe bilateral optic neuropathies. A point mutation in the mitochondrial ND4 gene accounts for 75% of all LHON cases. rAAV2/2-ND4 is a gene therapy enabling allotopic expression and delivery of the wildtype ND4 protein to mitochondria of retinal ganglion cells.

RESCUE (NCT02652767) and REVERSE (NCT02652780) are Phase III, randomized, double-masked, sham-controlled trials in which LHON subjects with the G11778A-ND4 mutation received a single unilateral intravitreal injection of rAAV2/2-ND4. Visual functions, retinal anatomy, and quality of life were monitored for 96 weeks following administration. 

A concurrent study with an equivalent injection on 3 non-human primates was performed. 

At Week 96, rAAV2/2-ND4-treated eyes of REVERSE subjects gained on average +15 ETDRS letters equivalent compared to baseline. Sham-treated eyes showed a similar improvement (+13 ETDRS letters), counter to expected natural history of the disease. In RESCUE, mean BCVA worsened to a nadir in both eyes, followed by a parallel improvement from Week 48 to Week 96. On average, rAAV2/2-ND4-treated eyes of RESCUE subjects gained +26 ETDRS letters equivalent compared to their nadir BCVA.

A clinically relevant response (CRR) from nadir was observed in at least one eye of 78% of REVERSE and 63% of RESCUE subjects. By comparison, a natural history study reported that only 28% of LHON subjects with the G11778A mutation had a spontaneous CRR from nadir.

The presence of rAAV2/2-ND4 in the fellow non-injected eye was demonstrated in the non-human primates.

Final results of RESCUE and REVERSE showed clinically meaningful improvements of visual functions. Improvement in the contralateral eye may be explained by the transfer of rAAV2/2-ND4 to the sham-treated eye.