FDA Clears First Clinical Trial of RNA Exon Editor Developed to Treat Stargardt Disease

Boston-based biotech Ascidian Therapeutics announced on Monday that the FDA has cleared its application to begin the first RNA-editing clinical trial in the United States. This milestone will allow Ascidian to test its RNA exon editor ACDN-01 in patients with Stargardt disease and other retinal diseases caused by mutations in the ATP binding cassette transporter gene, ABCA4.

Inspired by small sea creatures known as ascidians (or sea squirts), which are known to use RNA trans-splicing and alternative splicing to re-engineer their transcriptomes during metamorphosis, Ascidian Therapeutics was founded in 2020 to treat human disease by rewriting RNA through editing and replacing exons.

Targeting ABCA4 RNA to halt Stargardt disease

Stargardt disease is the most common form of inherited macular neurodegeneration, causing retinal dystrophy and progressive vision loss that typically begins in childhood or early in adulthood. The disease affects about 30,000 individuals in the United States alone, and can arise through more than 1,000 mutations in the ABCA4 gene, which encodes a protein involved in the visual cycle and transportation of toxic photoproducts out of the retina.

Currently, there are no treatments for Stargardt disease, and although restoring ABCA4 expression could help prevent (if adminstered before symptoms begin) or slow down disease progression, the large size of the gene, as well as the large number of identified disease-causing mutations have hampered progress in developing gene-replacement or gene-correction therapies.

Instead of correcting the disease-causing mutations through DNA editing, Ascidian's approach involves editing ABCA4 RNA.

ACDN-01 is delivered as a DNA construct via a single adeno-associated viral (AAV) vector, from which it is transcribed into mutation-free, exon-only RNA that is designed with a highly-specific binding domain. This allows the newly-transcribed RNA to bind to single-stranded pre-RNA (in this case from the ABCA4 gene), a process that is controlled by the cells' endogenous regulation systems. This results in the replacement of disease-causing exons with wild-type healthy mRNA, which is expressed at endogenous levels in the right cells and at the right time.

The exon-editing approach is expected to yield long-lasting therapeutic benefit without the risks associated with permanently editing genomic DNA. According to Ascidian Therapeutic's press release, ACDN-01 has demonstrated efficient and durable in vivo RNA editing in non-human primates as well as ex vivo RNA editing in human retinal explants. At the 2023 American Society of Gene and Cell Therapy (ASGCT) meeting, Ascidian presented data demonstrating that a single dose of ACDN-01 induced the production of full-length ABCA4 protein in a non-human primate retina.

The ACDN-01 trial

Enrolment for the open-label Phase 1/2 trial of ACDN-101, referred to as the STELLAR study, is expected to begin in the first half of 2024. The trial will evaluate the safety and efficacy of a single dose of ACDN-01 adminstered via sub-retinal injection.

As well as IND approval, the FDA has also granted Fast Track Designation to ACDN-01, which will allow the company to expedite its development of the novel therapeutic candidate via regular FDA feedback throughout the clinical development process.

We will share further updates about ACDN-01 and the STELLAR trial, as they emerge.

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