Results from a small clinical study suggest that EDIT-101, a CRISPR-based gene editing therapy for an inherited form of Leber’s congenital amaurosis (LCA), is safe and efficacious. The therapy did not cause any serious treatment or procedure-related adverse events, and there were no dose-limiting toxicities. Moreover, the therapy resulted in several clinically meaningful improvements in vision.

The study, a Phase I/II trial called BRILLIANCE, was led by principal investigator Eric Pierce, MD, PhD, of Mass Eye and Ear, a member of the Mass General Brigham healthcare system. It was sponsored by Editas Medicine, the company that developed EDIT-101, a CRISPR-based gene editing therapy for LCA10, which is a form of LCA due to mutations in the centrosomal protein 290 (CEP290) gene. EDIT-101 is administered via a subretinal injection to ensure that it is brought directly to photoreceptor cells.

Details from the trial appeared in the New England Journal of Medicine, in an article titled, “Gene Editing for CEP290-Associated Retinal Degeneration.” The article noted that the trial, which included the first patient to ever receive a CRISPR-based investigational medicine directly inside the body, was focused primarily on safety with a secondary analysis for efficacy. Participants were monitored every three months for one year, and then followed less frequently for two additional years. At visits, they would undergo a series of serum and vision tests to examine safety and efficacy outcome measures.

“EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5), and in 2 children 10 and 14 years of age at the intermediate dose,” the article reported. “[Our] study supports the safety of EDIT-101 to the extent that safety can be assessed in a small study.”

“Eleven participants (79%) had a clinically meaningful improvement in at least one of four key efficacy outcomes, whereas 6 (43%) had a clinically meaningful improvement in two or more outcomes,” the article added. “Four participants had a clinically meaningful improvement in the best-corrected visual acuity. Nearly half the participants (6 of 14) had a clinically meaningful improvement in cone photoreceptor function as assessed with the use of the full-field light-sensitivity threshold test, of whom all but one had a clinically meaningful improvement in at least one other outcome.”

“This research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials,” said Pierce, who is director of the Ocular Genomics Institute and Berman-Gund Laboratory for the Study of Retinal Degenerations at Mass Eye and Ear and Harvard Medical School. “While more research is needed to determine who may benefit most, we consider the early results promising.

“To hear from several participants how thrilled they were that they could finally see the food on their plates—that is a big deal. These were individuals who could not read any lines on an eye chart and who had no treatment options, which is the unfortunate reality for most people with inherited retinal disorders.”

Mutations in the CEP290 gene are the leading cause of inherited blindness taking place during the first decade of life. The mutations cause rod and cone photoreceptors in the eye’s retina to function improperly, which after some time will lead to irreversible vision loss. Pierce compares it to a small part of an engine breaking down, which eventually leads the entire engine to falter.

The CEP290 gene is larger than what traditional adeno-associated virus vector gene therapies, including one approved by the FDA for a different type of inherited vision loss, can accommodate. To develop an alternative approach, Editas Medicine began exploring how CRISPR-Cas9 technology could be used to tackle mutations in the large CEP290 gene. This work, which began in 2014, eventually led to the BRILLIANCE trial, which began in mid-2019.

“The results from the BRILLIANCE trial provide proof of concept and important learnings for the development of new and innovative medicines for inherited retinal diseases,” said Baisong Mei, MD, PhD, chief medical officer, Editas Medicine. “We’ve demonstrated that we can safely deliver a CRISPR-based gene editing therapeutic to the retina and have clinically meaningful outcomes.”

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