And the sheep shall lead them...

JERUSALEM—It started with a call from a concerned Israeli farmer. Beginning in 2003, the shepherd had noticed some sheep in his flock displaying signs of day blindness. Over the next five years, the prevalence in the herd grew—until he finally reached out to Dr. Ron Ofri, an associate professor of veterinary ophthalmology at Hebrew University of Jerusalem. Upon examination, Ofri determined the sheep all suffered from CNGA3 achromatopsia, a genetic mutation causing affected animals to experience blindness during the day and limited vision at night.

Together with scientists from the Hadassah Medical Center and the Agricultural Research Organization/Volcani Center, Ofri found that the sheep’s condition was the result of an identical genetic mutation to one gene that causes the same condition in humans. And, in another recent discovery, a veterinary clinician specializing in ovine retinal conditions uncovered a novel therapy that might see approval one day soon to treat day blindness in humans.

According to Ofri, “Achromatopsia (ACHM) is an inherited retinal disorder that specifically prevents cone photoreceptors from functioning. ACHM is characterized by severely reduced visual acuity of 20/200 or worse, disabling light sensitivity (photoaversion) and involuntary back-and-forth eye movements (nystagmus).”

ACHM occurs in approximately one in 30,000 people in the United States, with 92 percent of cases caused by mutations in CNGB3 and CNGA3 genes. The condition severely limits a person’s sight by preventing cone photoreceptors in the eye from functioning, leaving most affected individuals legally blind from birth.

Ofri and his team were completely surprised to find a large animal model of a mutation occurring in people, and decided to try gene therapy on the sheep. They injected a virus carrying a mutated copy of the gene beneath the retina of nine of the affected sheep, which began producing the missing protein and restoring day sight in the flock. According to a recent article published in Human Gene Therapy journal, now six years beyond the original treatment, results show significant, long-term improvement in cone function, demonstrating a robust rescue effect following a single treatment with a viral vector that provides episomal delivery of the transgene. In other words, the sheep experienced immediate recovery of cone photoreceptor function after a single injection, and can still see today.

“Confirmation of the concept of ‘once-in-a-lifetime’ gene therapy for genetic blindness depends on patient, careful studies such as these,” says the journal’s editor-in-chief Dr. Terence R. Flotte, who is also the Celia and Isaac Haidak Professor of Medical Education, and dean, provost and executive deputy chancellor of the University of Massachusetts Medical School. “Human gene therapy investigators in the field of retinal diseases should find these results very encouraging as they move forward in expanding clinical applications of the platform of rAAV gene therapy.”

And indeed, human researchers and regulators do find the results encouraging. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency’s Committee for Orphan Medicinal Products have awarded orphan drug designation to AAV-CNGA3, leading private companies such as MeiraGTx Holdings to embark on human clinical trials. In addition to AAV-CNGA3, MeiraGTx also has orphan designation in both the United States and European Union for three other inherited retinal disease gene therapy product candidates: AAV-CNGB3, AAV-RPGR and AAV-RPE65, all of which are in clinical development.

“Without any currently approved therapies [for achromatopsia], we are very pleased by the FDA’s decision and the recognition from the agency that those suffering from ACHM are in need of urgent treatment options,” said Dr. Alexandria Forbes, president and CEO of MeiraGTx. “This designation is the second important regulatory milestone we’ve received for AAV-CNGA3 in just two months, and we look forward to continuing the momentum in this program for those in need of relief from this debilitating disease.”

For Ofri, the human breakthrough initiated in his veterinary practice is thrilling. “It has been an amazing adventure to take a clinical case of a disease in sheep, and be able to run with it. To be a part of possibly alleviating day blindness in people is something I never thought, as a veterinarian, I would do. It is a great sense of satisfaction for me.”