CRISPR Therapy Shows Promise

Preliminary clinical results using CRISPR gene editing technology to treat patients with a form of Leber congen­ital amaurosis suggest the treatment is safe and clinical trials should expand, according to Professor Mark Pennesi.

Prof Pennesi worked with a US-based gene-editing company, Editas Medicine, to evaluate the treatment in patients with LCA10, a severe retinal degeneration with no current treatment plan. His clinic is one of five US centres that have recruited patients for the experimental treatment. The research group recently presented preliminary data from their phase 1/2 trial with an ascending dose study of the EDIT-101 CRISPR gene editing treatment for CEP290-related retinal degeneration.ⁱ

He noted cohort 1 (low dose) and cohort 2 (mid-dose) patients had no serious adverse effects and no dose-lim­iting toxicities. The most frequently reported adverse event was eye pain related to the surgical procedure. Key outcomes for BCVA (visual acuity), FST (full-field light stimulus threshold), and visual navigation included early efficacy signals in the mid-dose cohort, suggesting “posi­tive biological activity and potential early clinical benefits,” Prof Pennesi reported.

Up to 34 participants will be enrolled in up to 5 cohorts to evaluate up to 3 dose levels of EDIT-101, designed to elimi­nate the mutation on the CEP290 gene that results in retinal degeneration. Patients receive a non-randomised single administration of EDIT-101 through subretinal injection in one eye and are monitored every three months for a year, then less frequently for an additional two years. (Those interested in the study protocol can view it at clinicaltrials.gov using identifier NCT03872479.)

Despite these results, a subsequent press release from Editas Medicine dated 17 November 2022, stated: “[t]he results from the BRILLIANCE trial provide a proof of concept and import­ant learnings for our inherited retinal disease programmes. 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 enrolment, we have the patient community top of mind and are looking for a collaboration partner to advance this programme.”ⁱⁱ

CRISPR (clustered regularly interspaced short palindrom­ic repeats) is a recent gene editing technology that emerged from research into prokaryotic immune defence systems, then adapted and applied to multiple uses from agriculture to human gene therapy.

In brief, Cas9 (or “CRISPR-associated protein 9”) is an enzyme that uses gene sequences as a guide to recognise 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, awarded to Emmanuelle Charpentier and Jennifer Doudna.

Prof Pennesi presented at the 22nd EURETINA Congress in Hamburg.

Mark Pennesi MD, PhD is based at the Oregon Health & Science University (OHSU), Portland, Oregon, US. He is a Professor of Ophthalmology and Chief, Paul H Casey Ophthalmic Genetics Division. pennesim@ohsu.edu  

^{i, iii} Maeder ML et al., “Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10”. Nat Med. 2019 Feb; 25(2): 229–233.

ⁱⁱ“Editas Medicine Announces Clinical Data Demonstrating Proof of Concept of EDIT-101 from Phase 1/2 BRILLIANCE Trial.” www. editasmedicine.com, November 17, 2022. Editas Medicine. https:// ir.editasmedicine.com/news-releases/news-release-details/editas-medi­cine-announces-clinical-data-demonstrating-proof.