CRISPR gene editing shows promise for treating people with a form of hereditary blindness

Results from a groundbreaking clinical trial of CRISPR gene editing in 14 people with a form of hereditary blindness show the treatment is safe and led to measurable improvements in 11 of the treated participants. The phase 1/2 trial, called BRILLIANCE, was led by principal investigator Eric Pierce, MD, PhD, of Mass Eye and Ear, a member of the Mass General Brigham Health Care System, and was sponsored by Editas Medicine, Inc. The findings are reported on May 6 at The New England Journal of Medicine.

This research demonstrates that CRISPR gene therapy for hereditary vision loss is worth pursuing in research and clinical trials. While more research is needed to determine who might benefit the most, we think the early results are promising. Hearing from many attendees how excited they were to finally be able to see the food on their plates – that’s a big deal. These were people who couldn’t read a line on an eye chart and who had no treatment options, which is the unfortunate reality for most people with inherited retinal disorders.”

Eric Pierce, MD, PhD, 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

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 malformation (LCA) caused by mutations in centrosomal protein 290 (CEP290) gene. They underwent a single injection of a CRISPR/Cas9 genome-editing drug, EDIT-101, into one eye through a specialized surgical procedure. This trial, which involved the first patient ever to receive an investigational CRISPR-based drug directly into the body, focused primarily on safety with a secondary analysis of efficacy.

No serious treatment- or procedure-related adverse events were reported, and there were no dose-limiting toxicities. For effectiveness, the researchers looked at four measures: best-corrected visual acuity (BCVA); Dark-adapted full-field stimulus test (FST), visual function navigation (VNC, as measured by maze participants) and vision-related quality of life.

Eleven participants showed improvements in at least one of these outcomes, while six showed improvement in two or more. Four participants had a clinically significant improvement in BCVA. Six participants showed significant improvements in cone-mediated vision as indicated by FSTs, five of whom had improvements in at least one of the other three outcomes. Cone photoreceptors are used for daytime and central vision.

“The results from the BRILLIANCE trial provide proof of concept and important insights into the development of new and innovative drugs for inherited retinal diseases. We have demonstrated that we can safely deliver a CRISPR-based gene-editing therapy to the retina that is clinically meaningful results,” said Baisong Mei, MD, PhD, Chief Medical Officer, Editas Medicine.

Studies like this show the promise of gene therapy for treating incurable conditions. Mass General Brigham’s Institute for Gene and Cell Therapy helps translate scientific discoveries made by researchers into first-in-human clinical trials and, ultimately, into life-changing treatments for patients.

Exploring CRISPR as a treatment for an inherited retinal disorder

Mutations in CEP290 gene is the main cause of hereditary blindness that occurs during the first decade of life. The mutations cause the rod and cone photoreceptors in the retina of the eye to malfunction, which after some time will lead to irreversible vision loss. Pierce compares it to a small part of an engine breaking down, which eventually causes the entire engine to falter.

CRISPR-Cas9 is a gene-editing toolkit that acts as GPS-guided scissors to cut out a section of the mutated genome to leave a functional gene. For hereditary blindness, the goal was to inject CRISPR into the retina of the eye to restore the ability to produce the gene and protein responsible for the light-sensing cells.

The CEP290 The gene is larger than traditional adeno-associated virus (AAV) vector gene therapies can accommodate, including one FDA-approved for a different type of inherited vision loss. Genome-editing company Editas Medicine began investigating how to deal with it CEP290 mutation in 2014, conducting preclinical studies to determine whether a gene-editing approach such as CRISPR-Cas9 might be feasible to target these large gene mutations. This work led to the BRILLIANCE trial, which began in mid-2019.

The first patient to receive CRISPR therapy inside the body (in vivo) took place at the Casey Eye Institute at Oregon Health & Science University (OHSU), led by Mark Pennesi, MD, PhD.

“This trial shows that CRISPR gene editing has exciting potential for the treatment of hereditary retinal degeneration,” Pennesi said. “There is nothing more rewarding for a doctor than hearing a patient describe how their vision has improved after a treatment. One of our trial participants shared several examples, including being able to find their phone after misplace and know that his coffee maker is working by seeing his little lights, while these types of tasks may seem trivial to those with normal vision, such improvements can have a huge impact on the quality of life for those with low vision.

The second patient was treated at Mass Eye and Ear in September 2020, following delays caused by the COVID-19 pandemic. Additional participants were treated at three other trial sites: the Bascom Palmer Eye Institute, the WK Kellogg Eye Center, and the 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 medium-dose therapy, and another five received high-dose therapy. Two children, treated at CHOP under the leadership of Tomas S. Aleman, MD, received medium-dose therapy.

“Our patients are the first congenitally blind children to be treated with gene editing, which significantly improved their daytime vision. We hope the study will pave the way for treatments of younger children with similar conditions and further improvements in sight,” he said. Aleman, Irene Heinz-Given and John LaPorte Research Professor of Ophthalmology at Penn Medicine with the Scheie Eye Institute and a pediatric ophthalmologist at CHOP who served as principal investigator and co-author of the study. “This trial represents a milestone in the treatment of genetic diseases, specifically genetic blindness, offering an important alternative treatment when traditional forms of gene therapy, such as gene augmentation, are not an option.”

Participants were followed up every three months for one year and then less frequently for two additional years. At visits, they would undergo a series of serum and vision tests to look at safety and efficacy outcome measures.

In November 2022, Editas discontinued enrollment in the BRILLIANCE trial. Pierce and his colleagues are exploring working with other commercial partners to conduct additional trials in collaboration with Editas. The researchers hope that future studies can examine the ideal dosage, whether the 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 everyday life.