Leber’s Hereditary Optic Neuropathy: New Hope with Gene Therapy

Leber’s Hereditary Optic Neuropathy: New Hope with Gene Therapy
Clinical trial results suggest new therapies could restore vision lost to LHON.

Leber’s hereditary optic neuropathy (LHON) is a rare, maternally-inherited condition that causes degeneration of retinal ganglion cells and their axons. LHON is caused by specific mutations in mitochondrial DNA encoding ND1, ND4 or ND6 proteins. Although the condition usually begins in the teens or twenties, rare cases may appear in early childhood or later in adulthood. It affects approximately 1 in 50,000 people; currently there are approximately 300 cases identified in the U.S. Males are about four to five times more likely than females to be affected.

LHON is primarily characterized by bilateral, painless loss of central vision during young adulthood. Other symptoms can include neurologic abnormalities, movement disorders and multiple sclerosis-like muscle weakness. Vision loss occurs rapidly with LHON. Symptoms may begin in one eye first, followed a few weeks later by vision failure in the other eye. Peripheral vision generally remains intact, but central vision loss can be profound. Although not all carriers experience symptoms, for affected patients the vision loss is permanent and visual acuity rarely changes thereafter.

“Until recently, there’s been no effective treatment for Leber’s,” said Sean Donahue, M.D., Ph.D., Sam and Darthea Coleman Professor and vice president of clinical affairs at Vanderbilt Eye Institute (VEI). “The gene mutations were identified 30 years ago, but we haven’t had a delivery mechanism for gene therapy until now.”

Gene Therapy Study Moves to Clinical Trial

The gene delivery mechanism is GS010, a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) that encodes the human wild-type ND4 protein. A proprietary mitochondrial targeting sequence transports the messenger RNA from the nucleus directly to the outer membrane of the mitochondria. There, the ND4 proteins are synthesized and incorporated into the mitochondria. Wild-type ND4 proteins then integrate into Complex I of the respiratory chain and rescue the deficiency.

“We are the second site in the U.S. to offer the gene therapy,” Donahue said. “We’re the only site to offer it to children.”

A Phase 1/2 trial demonstrated that GS010 was well-tolerated in patients with LHON. Vanderbilt Eye Institute is an investigator site for a Phase 2 trial studying the efficacy and safety of bilateral intravitreal injection of GS010.

“Because we can handle both pediatric and adult patients at Vanderbilt, we are the second site in the U.S. to offer the gene therapy,” Donahue said. “We’re the only site to offer it to children.”

All study participants will receive the gene therapy in their eye with poorer vision. Half will also receive gene therapy in their better eye, and half will receive a placebo. Participants are required to make about a dozen visits to Vanderbilt over the course of the year for evaluation.

Quick Intervention Is Key to Reversal

“Leber’s progresses very rapidly,” explained Donahue, “A patient can go blind within a few hours. But because of the placebo condition, most IRBs won’t touch a trial like this. One of the great things about being at an institution like Vanderbilt is that there are incredible people here who understand the urgency and know how to navigate the system.”

When a 13-year-old patient came to VEI with vision loss, Donahue couldn’t treat him with the gene therapy because the age requirement for participants was 15. “We got a compassionate use protocol passed by the Vanderbilt IRB, and approval from the FDA and the company, so we were able to include him in the trial,” he said. “After four weeks of treatment, the patient already had three lines of vision improvement.”

“In the past, Leber’s has meant almost certain blindness in young adults. Hopefully, this therapy will be a tool for restoring vision loss in this rare disease.”

Donahue is optimistic about the gene therapy treatment. “In the past, Leber’s has meant almost certain blindness in young adults. Hopefully, this therapy will be a tool for restoring vision loss in this rare disease.”

For more information or to refer a patient to the trial, contact Scott Ruark, Clinical Trials Specialist, Vanderbilt Eye Institute: (615) 936-3465.