First-of-its-kind trial suggests CRISPR acting inside the body can be safe and effective

At a glance:

• In a small proof-of-concept trial, 11 out of 14 participants experienced improvement on at least one vision-related outcome, while six had improvements on two or more.
• The CRISPR-based therapy that delivered gene-editing medicine directly into the eye to repair gene function was found to be safe and effective.
• The findings support continued research and clinical trials of CRISPR therapies for inherited retinal disorders.

Results from a small proof-of-concept study indicate that CRISPR gene editing is safe and can improve vision in some people with inherited blindness.

In the multicenter clinical trial, 11 of the 14 individuals treated had measurable improvements on at least one key vision test, while six people experienced improvement on two or more vision outcomes.

The industry-sponsored study was led by Harvard Medical School researchers at Mass Eye and Ear. The team’s findings are reported May 6 in the New England Journal of Medicine.

All 14 participants in the trial had a form of the inherited retinal disorder Leber congenital amaurosis (LCA), one of the most common causes of childhood vision loss. LCA is associated with mutations in the centrosomal protein 290 (CEP290) gene.

The study’s primary focus was to determine whether the approach was safe and how well it worked before proceeding further. In light of the encouraging results, absence of harmful side effects, and notable improvements experienced by the participants, the strategy should be deployed in bigger clinical trials for inherited blindness, the research team said.

“This research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials,” said study principal investigator Eric Pierce, William F. Chatlos Professor of Ophthalmology and director of the Ocular Genomics Institute in the Department of Ophthalmology at Mass Eye and Ear and Harvard Medical School.

Pierce also noted that although more research is needed to see which patients may benefit most from the treatment and to calibrate the most effective dose, the early results are promising and can pave the way to CRISPR-based treatments for other forms of genetic blindness.

CRISPR-Cas9 gene editing employs guide RNAs that act like GPS guides to bring the Cas9 enzyme to a targeted location in the genome. Cas9 then cuts the genome, enabling the cell’s natural genetic machinery to delete unwanted mutations or repair malfunctioning genes. For the BRILLIANCE trial Editas Medicine developed EDIT-101, which uses two guide RNAs to flank a mutation in CEP290, allowing the mutation to be removed and the function of CEP290 to be restored.

The trial included the first-ever patient to receive a gene-editing medicine directly inside the body in 2019, although since then other studies using this approach that began later have been published. Until recently, gene-editing modifications used therapeutically have been done outside the body and then administered to the patient in the form of already genetically edited cells. This is still the case with most gene-editing therapies in use.

The promise of CRISPR as a treatment for a range of serious, intractable diseases is huge, but the technique is still very new. So far, only about 250 people worldwide have received any kind of experimental CRISPR-based therapies for any disease, said CRISPR pioneer Jennifer Doudna during a recent lecture at HMS. Doudna, who won the 2020 Nobel Prize in chemistry for her work on CRISPR-Cas9, was not involved in the NEJM study.

In addition to Mass Eye and Ear, the study involved patients and researchers from Oregon Health & Science University, Bascom Palmer Eye Institute, W.K. Kellogg Eye Center, the Children’s Hospital of Philadelphia, the Hospital of the University of Pennsylvania, and Editas Medicine, a company focused on developing gene-editing medicines and co-founded by George Church, the Robert Winthrop Professor of Genetics in the Blavatnik Institute at HMS, along with colleagues from Harvard and the Broad Institute of MIT and Harvard .

For this trial, the goal was to inject a CRISPR medicine that could reach the retina and restore the function of a key gene and protein that enable light-sensing cells to work properly in people with LCA. All 14 trial participants, including 12 adults (ages 17 to 63) and two children (ages 10 and 14), received a single injection of the EDIT-101 gene-editing medicine designed to repair CEP290 in one eye.

“To hear from several participants how thrilled they were that they could finally see the food on their plates — that is a big deal,” Pierce said. “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.”

No serious adverse events related to the treatment or procedure were reported, nor were there any toxic effects that would require a lower dose of the therapy.

To determine whether the treatment worked, the researchers looked at four measures: visual acuity, the familiar test that determines the smallest letters a person can see on an eye chart using corrective lenses; dark-adapted full-field stimulus testing, which uses flashes of light to measure retinal sensitivity; visual function navigation, done by having participants complete a maze in varying light levels; and vision-related quality of life, which gauges an individual’s ability to complete everyday activities, as well as their social and emotional well-being.

Eleven participants had improvements on at least one of those outcomes, while six experienced improvements in two or more.

Exploring CRISPR as a therapy for inherited retinal disorders

Mutations in the CEP290 gene are the leading cause of inherited retinal blindness that occurs during childhood. The mutations cause rod and cone photoceptors in the retina to function improperly, which, over time, leads to irreversible vision loss. Pierce compares it to a small part of an engine breaking down, which eventually causes the entire engine to falter.

The first person to receive a CRISPR treatment inside the body (in vivo) was a patient at another BRILLIANCE trial site, the Casey Eye Institute at Oregon Health & Science University. The procedure took place under the leadership of study co-author Mark Pennesi.

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

Two adults received low-dose therapy, five received mid-dose, and another five received a high-dose treatment. Two children, treated at Children’s Hospital of Philadelphia under the leadership of study co-author Tomas Aleman, received a mid-dose treatment. 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.

The children in this study, the first to be born blind and treated with gene editing, experienced notable improvement.

“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 November 2022, Editas paused enrollment in the BRILLIANCE trial to find another commercial collaborator to advance the research. The researchers hope future studies can examine ideal dosing, clarify whether a treatment effect is more pronounced in certain age groups, and can include refined endpoints to measure the effects of improved cone function on activities of daily living.