Dr Patrick Yu-Wai-Man

A phase III clinical trial of gene therapy for the treatment of Leber hereditary optic neuropathy (LHON) has demonstrated a bilateral improvement of vision after injection of just one eye.

The trial, led by Dr Patrick Yu-Wai-Man and published in Science Translational Medicine, used adeno-associated viral (AAV) vectors and a recombinant AAV, rAAV2/2-ND4, in 37 subjects with LHON and bearing the MT-ND4 mitochondrial DNA mutation. Although only one eye in each subject was treated (the control eye received a sham treatment), Dr Yu-Wai-Man reported sustained vision improvement in both eyes 96 weeks after treatment. At that time 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye and 29 subjects (78%) had an improvement in vision in both eyes.

“We thought that, if there was going to be an effect, it would be isolated to that eye and then the other one would be the perfect internal control,” Dr Yu-Wai-Man told The Scientist. “But as it turns out, that wasn’t the case.”

To investigate the mechanism of the observed bilateral effects, Yu-Wai-Man’s team injected the therapeutic virus into one eye in each of three monkeys. After three months, viral DNA was detected in the optic nerve of the non-injected eyes, supporting but not proving the theory that the viral vector transferred the wildtype protein to the untreated eye.

While there are clear clinical benefits to being able to treat both eyes with a single injection, the trial’s findings also imply that the use of one eye as a true control in similar scenarios could be problematic.