CRISPR gene editing is safe and could improve vision in people with inherited blindness, according to preliminary test results from a multi-center clinical trial in which 11 of 14 participants showed significant improvements in at least one vision test. key, and six of them recorded improvements in two or more visual outcomes.
The study was led by researchers at Harvard Medical School in Mass Eye and Ear. All participants suffered from Leber congenital amaurosis (LCA), a genetic disease that primarily affects the retina – the part of the eye responsible for capturing light and sending images to the brain – and is one of the most serious causes of vision loss since birth or early childhood.
Children affected with this disease may show signs of blindness from birth or develop significant visual problems during the first months of life. This condition is linked to mutations in the centrosomal protein 290 (CEP290) gene, which prevent photoreceptors in the retina – which are light-sensitive cells – from developing properly or functioning properly, leading to a loss of progressive vision.
The primary goal of the study was to determine the safety of the approach and its effectiveness before moving to later phases. The results have been published in the New England Journal of Medicine and show an absence of harmful side effects and notable improvements in the participants, so the research team suggests that this strategy be implemented in larger clinical trials for hereditary blindness.
“This research confirms that CRISPR gene therapy for inherited vision loss is worth continuing to explore in future research and clinical trials,” said the study’s principal investigator, Eric Pierce, William F. Chatlos Professor of Ophthalmology and director of the Institute of Ophthalmology. Ocular Genomics in the Department of Ophthalmology at Mass Eye and Ear and Harvard Medical School (HMS).
Pierce also noted that while more research is needed to determine which patients might benefit most from the treatment and to adjust the most effective dose, preliminary results are promising and could open the way to CRISPR-based treatments for other forms of genetic blindness.
A CRISPR gene-editing medicine designed to restore sight
CRISPR-Cas9 gene editing uses guide RNA that acts as a GPS to direct the Cas9 enzyme to a specific location in the genome. Cas9 cuts through the genome, allowing the cell’s natural genetic machinery to remove unwanted mutations or repair defective genes. For the BRILLIANCE trial, Editas Medicine developed EDIT-101, which uses two guide RNAs to flank a mutation in CEP290, allowing its elimination and restoration of CEP290 function.
The trial included the first patient to receive a gene-editing medicine directly into the body in 2019, although other studies using this approach have since been published. Until recently, gene editing modifications used therapeutically were performed outside the body and then administered to the patient in the form of already gene-edited cells. This remains true for most gene editing therapies in use.
The potential of CRISPR as a treatment for a range of serious and untreatable diseases is enormous, but the technique is still very new. To date, only about 250 people worldwide have received any type of CRISPR-based therapies for any disease, CRISPR pioneer Jennifer Doudna said during a recent conference at HMS. Doudna, who won the 2020 Nobel Prize in chemistry for her work on CRISPR-Cas9, was not involved in the NEJM study.
The children in this study, the first to be born blind and treated with gene editing, experienced notable improvement
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 allows light-sensitive cells to function properly in people with ACL. The 14 trial participants, including 12 adults (aged 17 to 63) and two children (aged 10 and 14), received a single injection of the gene-editing drug EDIT-101 designed to repair CEP290 in one eye.
“Hearing from several participants how excited they were to finally be able to see the food on their plates is a big deal,” Pierce said. “These were people who couldn’t read any lines on an eye chart and had no treatment options, which is the unfortunate reality for most people with inherited retinal disorders.”
To determine whether the treatment worked, researchers evaluated four measures: visual acuity, a familiar test that determines the smallest letters a person can see on an eye chart while wearing corrective lenses; dark-adapted full-field stimulus tests, which use flashes of light to measure retinal sensitivity; visual function navigation, performed by having participants complete a maze at varying light levels; and vision-related quality of life, which assesses the individual’s ability to complete daily activities, as well as their social and emotional well-being.
Eleven participants showed improvements in at least one of those outcomes, while six experienced improvements in two or more. The children in this study, the first to be born blind and treated with gene editing, experienced notable improvement. Additionally, no serious adverse events related to the treatment or procedure were reported, nor were there any toxic effects requiring a lower dose of therapy.
The researchers hope that future studies can identify the ideal dose, determine whether a treatment effect is more evident in certain age groups, and can include refined endpoints to measure the effects of improved cone function in exercise activities. daily life. “Our hope is that the study paves the way for treatments of younger children with similar conditions and further improvements in vision,” Aleman concludes.
