CRISPR Therapy Shows Some Benefit in Leber Congenital Amaurosis


A competing RNA-based therapy for LCA10 is currently being evaluated in a phase 2/3 trial.

Editas Medicine has announced initial positive data from their ongoing phase 1/2 BRILLIANCE trial of EDIT101, a CRISPR-based therapy, for the potential treatment of Leber congenital amaurosis 10 (LCA10).1

Editas reported data from 5 participants, 2 treated in the low-dose cohort and 3 in the mid-dose cohort, followed-up for at least 3 months. One participant in the mid-dose cohort improved in best corrected visual acuity (BCVA) by 0.7 logMAR at month 1.5 and this improvement was sustained at month 6. Another participant exhibited a stable BCVA and improvement in retinal sensitivity at month 3.

“The preliminary results shared today support our belief that EDIT-101 has the potential to provide meaningful benefits to people living with CEP290-related retinal degeneration or LCA10. A positive safety profile has been observed through up to 15 months, with mostly mild adverse events primarily related to the procedure of retinal injection. The safety profile has allowed us to start enrolling and treating subjects in both the high-dose adult cohort and the mid-dose pediatric cohort,” Lisa Michaels, MD, executive vice president and chief medical officer, Editas Medicine, said in a statement.1 “Early observations from individuals who were treated in the mid-dose cohort show clinical evidence that gene editing has occurred, demonstrated by visual improvements, as measured by full-field light sensitivity threshold (FST) testing, best corrected visual acuity (BCVA), or improvement in their ability to navigate standardized navigation courses with varying levels of difficulty.”

These data were presented at the XIXth International Symposium on Retinal Degeneration by BRILLIANCE principal investigator Mark Pennesi, MD, PhD. The 2 participants in the mid-dose cohort previously mentioned had up to 6 months of follow-up and showed improvements in BCVA, FST, and Visual Function Navigation (VNC). Both participants had improved retinal sensitivity by FST in the study eye relative to the untreated eye. The first participant demonstrated improvement on the VNC with a 5-level improvement in mobility.

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“I am encouraged by these initial results, which indicate this investigational gene editing treatment has been well-tolerated in this trial’s participants thus far and may also help improve sight for people with mutations in the CEP290 gene. Being able to edit genes inside the human body is incredibly profound, and I hope to be able to offer my LCA patients new treatment options involving gene editing in the future,” Pennesi, who is a professor of molecular and medical genetics, Kenneth C. Swan Endowed Professor of Ophthalmology, and Paul H. Casey Ophthalmic Genetics Division Chief at Casey Eye Institute, Oregon Health & Science University, added.1

Although the data reported are from a small number of patients, BRILLIANCE is still enrolling up to 5 cohorts testing 3 dose levels, with a target enrollment of 18 adult and pediatric participants. Participants in the trial receive a single subretinal injection of EDIT-101 in 1 eye and are then monitored every 3 months for the first year after treatment and less frequently for another 2 years.

Mild adverse events (AEs) did occur, mostly relating to the surgical procedure and subretinal injection. No severe dose-limiting toxicities were identified. Investigators did observe mild anterior chamber inflammation which was then controlled with oral steroids. No Cas9-specific antibody or T-cell response, treatment-related cataracts, edema, or retinal thinning have been observed.

“We will continue to follow the trial participants prospectively and collect clinical measures to allow us to determine the extent of both continued and durable improvements,” Michaels added.1 “These encouraging results provide a proof of concept on our in vivo gene editing platform and increase Editas’ confidence in the broad potential of our gene editing technology to address additional serious diseases.”

However, Editas isn’t alone in their pursuit to treat LCA10. Another therapy currently being investigated is sepofarsen (QR110; ProQR Therapeutics), an RNA therapy designed to bind to and correct the RNA affected by the mutated CEP290 gene in LCA10. The therapy is currently being investigated in 36 participants in the phase 2/3 Illuminate study (NCT03913143), which completed enrollment in January 2021.2

A previous phase 1/2 study (NCT03140969) demonstrated a mean change in BCVA of –0.93 LogMAR (9 lines/45 letters on ETDRS) from baseline at month 12 in 6 participants. Secondary end points in FST and mobility were also met.

“If approved, sepofarsen has the potential to be the first therapy to address this high unmet medical need for patients who would otherwise face blindness,” Aniz Girach, MD, chief medical officer, ProQR, said in a statement at that time.2 “We look forward to sharing the top-line results in the first half of 2022.”

1. Editas Medicine announces positive initial clinical data from ongoing phase 1/2 BRILLIANCE clinical trial of EDIT-101 For LCA10. News release. September 29, 2021.
2. ProQR completes enrollment of its pivotal trial of sepofarsen for the treatment of LCA10. News release. ProQR. January 7, 2021. 
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