Skip to content

Pausing of CRISPR gene editing therapy for LCA CEP290-related retinal degeneration from >15 patients

Despite positive initial clinical data from an ongoing open label Phase I/II “BRILLIANCE” study, named EDIT-101, a CRISPR-based experimental treatment for the treatment of Leber congenital amaurosis 10 (LCA10), the study’s sponsor (Editas Inc.) has decided to pause the study.  The study was designed to assess the safety, tolerability, and efficacy of EDIT-101 in up to 18 patients enrolling up to five cohorts testing up to three dose levels in the open label, multi-center study. Both adult and pediatric patients (3 – 17 years old) with a range of baseline visual acuity assessments were eligible for enrollment to receive a single administration via subretinal injection in one eye (NCT#03872479). LCA10 is an autosomal recessive ciliopathy arising from the CEP290 intronic variant c.2991+1655A.G [p.Cys998X]), one of the most common mutations from LCA.  LCA10-causing mutation is IVS26 – an adenine to guanine point mutation located within intron 26 (c.2991+ 1655A> G) that creates a novel splice donor site, resulting in the inclusion of a 128 base pair (bp) cryptic exon (exon X) in the messenger RNA (mRNA) creating a premature stop codon. EDIT-101 technology is aimed to apply CRISPR gene-editing to correct this problem.


In brief, CRISPR (an acronym for clustered regularly interspaced short palindromic repeats) is a recent gene editing technology that has emerged from research into prokaryotic immune defense systems, and then adapted and applied to multiple uses from agriculture to human gene therapy.  The technology itself dates back to the late 1980s whereby gene editing tools may be viewed as part of a continuum, dating back to the discovery and introduction of antisense, ribozymes, aptamers, RNAi, zinc fingers, TALENs and more recently, “CRISPR/Cas9”.  This is not to suggest a hierarchy from antisense to CRISPR/Cas9, but rather reflects a loose chronology in the discovery of new gene-editing tools.  In brief, Cas9 (or “CRISPR-associated protein 9”) is an enzyme that uses gene sequences as a guide to recognize and cleave specific strands of DNA complementary to a CRISPR sequence, not unusual to a copy and paste process in a writing document. The development of this gene editing technique was recognized by the Nobel Prize in Chemistry in 2020 which was awarded to Emmanuelle Charpentier and Jennifer Doudna.  RNAi previously was developed by Fire & Mello recognized by the Nobel Prize in Physiology or Medicine in 2006.


More recently, preliminary results indicated that three out of 14 treated subjects met a responder threshold having experienced clinically meaningful improvements in BCVA (logMAR >0.3) and demonstrated consistent improvements in two of following three additional endpoints: full field sensitivity test (FST), visual function navigation course (VFN), or the visual function quality of life (VFQ).  Regardless, the small market size of the population for the proposed EDIT-101 treatment may be challenging to conduct the subsequent route to market, including their costs. In follow-up to their announcement, Dr. Gilmore O’Neill, M.B., M.M.Sc. (led by EDIT-101) stated, “the results from the BRILLIANCE trial provide a proof of concept and important learnings for our inherited retinal disease programs. We’ve demonstrated that we can safely deliver a CRISPR-based gene editing therapeutic to the retina and have clinically meaningful outcomes.  While we will not progress EDIT-101 on our own and have made the decision to pause enrollment, we have the patient community top of mind and are looking for a collaboration partner to advance this program.”