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CRISPR experimental treatment on a Phase 1/2 study for LCA10 patients report meaningful improvements.

Clinical researchers based in Oregon Health and Science University (OHSU), Portland and the Ocular Genomics Institute, Mass Eye and Ear, Harvard University, have published the results of a Phase 1/2 clinical trial using a CRISPR gene-editing treatment for patients diagnosed with Leber congenital amaurosis (LCA10).  The peer-reviewed report, published in the journal New England Journal of Medicine (May 6th, 2024, DOI:10.1056/NEJMoa2309915), showed meaningful improvements of up to 6 of 14 participants, measured by visual acuity (BCVA),  red-light full-field stimulus (FST), mobility testing and quality-of-life questionnaires.  The CRISPR gene-editing treatment, named as “EDIT-101”, have been found to be safe and researchers suggested that their proof of concept supports, “further research into CRISPR-Cas9–mediated therapies for certain other inherited retinal degenerations and inherited diseases”.

CRISPR (clustered regularly interspaced short palindromic repeats) is a family of DNA sequences that have been adapted as a gene-editing tool for disease treatment.  A CRISPR-associated protein 9 (Cas9) provides an enzyme that can then be used to engineer DNA sequences as a guide to recognize and open up specific strands of DNA complementary to almost any sequence desired.  Essentially, the technology provides a “cut and paste” editing-tool to be used as a gene therapy treatment.  LCA10 is one of the most frequent types of Leber congenital amaurosis, arising from mutations in a gene, CEP290, a centrosomal protein functioning in photoreceptor ciliary transport, and in the current Phase 1/2 study, the LCA10 treatment (EDIT-101) was designed to permanently remove the CEP290 -IVS26 variant and subsequently allow the corrected sequence be translated to a functional CEP290 protein.

Lead PI Mark Pennesi, MD, PhD located at the Casey Eye Institute, Oregon Health and Science University, Portland

The clinical trial used 5 cohorts (adult and pediatric patients) using three doses. – low, medium and high doses with an open-label non-randomised design recruiting patients aged from 9 year to 63 years (female 64%, male 36%).  The low-dose had 6×1011 vg/mL, mid-dose of 1×1012 vg/mL, and the high-dose of 3×1012 vg/mL. The BCVA results reported that 4 of 14 participants (29%) had improvements reached the prespecified threshold for clinically meaningful improvement, of at least 0.3 logMAR.  For the red-light FST, the sensitivity threshold improved by at least 0.6 log cd-sec per meter2 in the study eyes in 6 of 14 participants (43%), considered to be visually meaningful.  The visual function navigation test showed an improvement from baseline of at least 3 points in the score (visually meaningful difference) with an observation of 4 of 14 participants (29%) and finally, a vision-related quality of life evaluation reported that 43% of the participants (6 of 14) was at least 4 points higher at follow-up than at baseline (meaningful improvement).  Commenting on the publication, Mark Pennesi, M.D., Ph.D., Oregon Health & Science University’s lead scientist for the trial stated that, “this trial shows CRISPR gene editing has exciting potential to treat inherited retinal degeneration.  There is nothing more rewarding to a physician than hearing a patient describe how their vision has improved after a treatment. 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”.