Ascidian to launch clinical trial for Stargardt disease RNA editing therapy

Stargardt disease, an inherited form of macular degeneration caused by mutations in the ABCA4 gene, affects approximately 30,000 people in the US. It is characterized by the accumulation of toxic byproducts from vitamin A metabolism in the retina, ultimately leading to retinal cell death and central vision loss. People with Stargardt disease can lose the ability to read, drive, and recognize faces. The condition is usually diagnosed in children or young adults, but age of onset, severity, and rate of progression can vary.

Ascidian Therapeutics has received authorization from the US Food and Drug Administration to launch a Phase 1/2 clinical trial for ACDN-01, the company’s RNA editing therapy for people with Stargardt disease. The company plans to begin enrollment for the clinical trial, known as STELLAR, during the first half of 2024.

Unlike genetic therapies that deliver or edit an entire healthy gene (DNA) to replace the mutated gene, ACDN-01 rewrites RNA, the genetic message derived from DNA that cells read to make proteins. Healthy proteins are essential to the survival and function of all cells in the body, including those of the retina. ACDN-01 specifically rewrites RNA exons, the coding regions of DNA where mutations are most likely to occur for the ABCA4 gene. Ascidian estimates that ACDN-01 can address mutations in ABCA4 for a significant percentage of people with Stargardt disease because the editing replaces a large number of exons, all at once.

By targeting Stargardt disease at the RNA level, ACDN-01 overcomes two limitations with therapeutic approaches that replace or edit DNA. First, it bypasses the challenge of delivering the large ABCA4 gene, which exceeds the capacity of the viruses used to deliver genetic material known as adeno-associated viruses (AAVs) that are typically used in retinal gene therapies. Also, RNA editing avoids permanent, off-target DNA editing which is a potential risk with gene editing.

ACDN-01 is delivered by a one-time, subretinal (under the retina) injection. The emerging treatment is the first RNA exon editor to enter clinical development for any disease and the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease. ACDN-01 has demonstrated efficient and durable RNA exon editing in a large animal model and in human retinal explants, a simplified lab model of the retina.

Edited by Miriam Kaplan, PhD

Source: Foundation Fighting Blindness, Eye on the Cure Research News, February 1, 2024; see source article