About 79% of clinical trial participants experienced measurable improvement after receiving experimental CRISPR-based gene editing that is designed to fix a rare form of blindness, according to the specialists involved in the recent research.
“This trial shows CRISPR gene editing has exciting potential to treat inherited retinal degeneration,” said Mark Pennesi, MD, PhD, a corresponding author on the paper, an ophthalmologist and Oregon Health & Science University’s lead scientist for the phase 1/2 BRILLIANCE trial.
“There is nothing more rewarding than hearing a patient describe how their vision has improved after a treatment,” he said. “One of our 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.”
The BRILLIANCE trial evaluated the safety and effectiveness of EDIT-101, an experimental gene editing treatment developed by Editas Medicine that uses CRISPR technology. The experimental treatment was designed to edit a mutation in the CEP290 gene, which provides instructions to create a protein that is critical for sight.
The findings were published in The New England Journal of Medicine.
No FDA treatment
People with this gene mutation have a rare condition that is commonly called Leber Congenital Amaurosis, or LCA, Type 10, for which there is currently no Food and Drug Administration-approved treatment. LCA’s various types occur in about two or three out of 100 000 newborns.
The OHSU Casey Eye Institute treated the trial’s first participant in early 2020. That procedure also marked the first time that CRISPR had been used to edit genes within the human body, called in vivo gene editing.
The new paper describes the study’s findings until February 2023 and details how the trial’s 14 participants – 12 adults and two children – responded to receiving EDIT-101 in one eye. Key results include:
• 11 participants, about 79%, showed improvement in at least one of four measured outcomes.
• six participants, about 43%, showed improvement in two or more outcomes.
• six participants, about 43%, reported improved vision-related quality of life.
• four participants, about 29%, had clinically meaningful improvement in visual acuity, or how well they could identify objects or letters on a chart.
• There were no serious adverse events related to the treatment.
• Most adverse events were mild or moderate, and all have since been resolved.
Four specific outcomes were used to evaluate the experimental treatment's effectiveness:
• Visual acuity
• How well participants saw coloured points of light while looking into a specialised device, which scientists call a full-field test
• How well participants navigated a research maze with physical objects and varying amounts of light
• How much participants reported experiencing improved quality of life
Further research for a future treatment
In November 2022, trial sponsor Editas Medicine announced that it was pausing the trial’s enrolment and would seek another partner to continue the experimental therapy’s development.
Pennesi 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 impacts on activities of daily living.
“This research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials,” said Massachusetts Eye & Ear ophthalmologist Eric Pierce, MD, PhD, who is also a corresponding author.
“While more research is needed to determine who may benefit most, we consider the early results promising. 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.”
“Our patients are the first congenitally blind children to be treated with gene editing, which significantly improved their daytime vision,” said third corresponding author Tomas Aleman, MD, a paediatric ophthalmologist at the Children’s Hospital of Philadelphia and the University of Pennsylvania’s Scheie Eye Institute.
“This trial represents a landmark in the treatment of genetic disease, in specific genetic blindness, by offering important alternative treatment when traditional forms of therapy, such as gene augmentation, are not an option.”
Study details
Gene Editing for CEP290 -Associated Retinal Degeneration
Eric Pierce, Tomas Aleman, Mark Pennesi et al.
Published in The New England Journal of Medicine on 6 May 2024
Abstract
Background
CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).
Methods
We performed a phase 1–2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora–Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire–25 (in adults) or the Children’s Visual Function Questionnaire (in children).
Results
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 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.
Conclusions
The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1–2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes.
NEJM article – Gene Editing for CEP290 -Associated Retinal Degeneration (Open access)
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