Study: CRIPSR gene editing leads to improvements in vision for people with inherited blindness

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The results from a clinical trial of CRISPR gene editing in 14 individuals with a form of inherited blindness show that the treatment is safe and led to measurable improvements in 11 of the participants treated.

According to a news release,1 the phase 1/2 trial called BRILLIANCE, was led by principal investigator Eric Pierce, MD, PhD, of Massachusetts Eye and Ear, a member of the Mass General Brigham healthcare system, and sponsored by Editas Medicine, Inc. Findings are reported May 6th in The New England Journal of Medicine.²

Pierce, director of Ocular Genomics Institute and Berman-Gund Laboratory for the Study of Retinal Degenerations at Mass Eye and Ear and Harvard Medical School, pointed out in the news release the research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials.

“While more research is needed to determine who may benefit most, we consider the early results promising,” Pierce said in the release. “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.”

According to the Massachusetts Eye and Ear news release, all 14 trial participants, including 12 adults (ages 17 to 63) and two children (ages 10 and 14), were born with a form of Leber Congenital Amaurosis (LCA) caused by mutations in the centrosomal protein 290 (CEP290) gene. The participants received a single injection of EDIT-101, a CRISPR/Cas9 genome editing medicine, in 1 eye via a specialized surgical procedure. The trial, which included the first patient to receive a CRISPR-based investigational medicine directly inside the body, focused primarily on safety with a secondary analysis for efficacy.

The researchers noted in the news release that there were no serious treatment or procedure-related adverse events reported, nor were there any dose-limiting toxicities.

As they examined efficacy, the researchers looked at 4 measures: best-corrected visual acuity (BCVA); dark-adapted full-field stimulus testing (FST), visual function navigation (VNC, as measured by a maze participants completed), and vision-related quality of life.

Eleven participants demonstrated improvements in at least one of those outcomes, while six demonstrated improvement in 2 or more. Four participants had clinically meaningful improvement in BCVA. The FSTs showed that 6 participants had meaningful improvements in cone-mediated vision. Of those, 5 had improvements in at least 1 of the 3 other outcomes, according to researchers.

“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,” Baisong Mei, MD, PhD, chief medical officer at Editas Medicine, said in the news release. “We’ve demonstrated that we can safely deliver a CRISPR-based gene editing therapeutic to the retina and have clinically meaningful outcomes.”

CRISPR as an inherited retinal disorder treatment

The researchers noted in the news release mutations in the CEP290 gene are one of the primary causes of inherited blindness, generally occurring during an individual’s first 10 years of live. The mutations drive malfunctions in the cone and rod photoreceptors in the retina, and eventually lead to vision loss in patients diagnosed with the disease. Pierce compares it to a small part of an engine breaking down, which eventually leads the entire engine to falter.

CRISPR-Cas9 is a gene editing toolkit that acts as a GPS-guided scissor to cut a portion of the mutated genome to leave a functional gene. For inherited blindness, the goal was to inject CRISPR to reach the eye’s retina to restore the ability to produce the gene and protein responsible for light-sensing cells.¹

Moreover, the researcher noted the CEP290 gene is larger than what traditional adeno-associated virus (AAV) vector gene therapies, including one FDA-approved for a different type of inherited vision loss, can accommodate.

Editas Medicine, a genome editing company, started to explore how to tackle the CEP290 mutation 10 years ago, conducting preclinical studies to determine whether a gene editing approach like CRISPR-Cas9 might be feasible to target these large gene mutations. This work led to the BRILLIANCE trial, which began in mid-2019.¹

The first patient to receive a CRISPR treatment inside the body (in vivo) took place at the Casey Eye Institute at Oregon Health & Science University (OHSU), under the leadership of Mark Pennesi, MD, PhD.

“This trial shows CRISPR gene editing has exciting potential to treat inherited retinal degeneration,” Pennesi said in the news release. “There is nothing more rewarding to a physician than hearing a patient describe how their vision has improved after a treatment.”

Pennesi pointed out 1 of the trial participants has shared several examples, including being able to find their phone after misplacing it and knowing that their coffee machine is working by seeing its small lights.

“While these types of tasks might seem trivial to those who are normally sighted, such improvements can have a huge impact on quality of life for those with low vision,” he noted in the release.

After delays resulting from the COVID-19 pandemic, the second patient was treated at Mass Eye and Ear in September 2020. Additional participants were treated across 3 other trial sites: Bascom Palmer Eye Institute, W.K. Kellogg Eye Center, and Scheie Eye Institute at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania. Two adults received low-dose therapy, five received mid-dose, and another five received a high-dose treatment. Two children, treated at CHOP under the leadership of Thomas S. Aleman, MD, received a mid-dose treatment.

Aleman, the Irene Heinz-Given and John LaPorte Research Professor in Ophthalmology at Penn Medicine with the Scheie Eye Institute and a pediatric ophthalmologist at CHOP, served as a site principal investigator and study co-author. He explained that the patients are the first congenitally blind children to be treated with gene-editing, which significantly improved their daytime vision.

“Our hope is that the study will pave the road for treatments of younger children with similar conditions and further improvements in vision,” Aleman said in the news release. “This trial represents a landmark in the treatment of genetic diseases, in specific, genetic blindness, by offering an important alternative treatment, when traditional forms of gene therapy, such as gene augmentation, are not an option.”

Researchers noted in the news release the participants were monitored every 3 months for 1 year, and were monitored less frequently for 2 years. During visits, they would receive a series of serum and vision tests to examine safety and efficacy outcome measures.

In November 2022, Editas paused enrollment on the BRILLIANCE trial. Pierce and colleagues are exploring working with other commercial partners to conduct additional trials, in collaboration with Editas. The researchers hope future studies can examine ideal dosing, whether a treatment effect is more pronounced in certain age groups such as younger patients, and include refined endpoints to measure the effects of improved cone function on activities of daily living.¹

The research, according to the news release, was funded Editas Medicine, and was also supported by the National Institute of Health P30 EY014104 core grant to Mass Eye and Ear, P30 EY010572 core grant, the Malcolm M. Marquis MD Endowed Fund for Innovation, and an unrestricted grants from Research to Prevent Blindness to Casey Eye Institute and the Scheie Eye Institute. Additional support was provided by the Irene Heinz Given and John La Porte Given Endowment, and Hope for Vision.¹

References:

1. CRIPSR gene editing leads to improvements in vision for people with inherited blindness, clinical trial shows. EurekAlert! Published May 7, 2024. Accessed May 9, 2024. https://www.eurekalert.org/news-releases/1043333

2. Eric A. Pierce, MD, PhD, Tomas S. Aleman, MD, Kanishka T. Jayasundera, MD, Bright S. Ashimatey, OD, PhD, Keunpyo Kim, PhD, Alia Rashid, MD, Michael C. Jaskolka, PhD,and Mark E. Pennesi, MD, PhD; Gene Editing for CEP290-Associated Retinal Degeneration. The New England Journal of Medicine. Published May 6, 2024. Accessed May 9, 2024. DOI: 10.1056/NEJMoa23099