A new company, Ascidian Therapeutics, is launching with a focus on treating human diseases by rewriting RNA. With an initial focus on replacing mutated exons at the RNA level, Ascidian’s technology enables targeting of large genes and genes with high mutational variance while maintaining native gene expression patterns and levels. This approach is designed to reduce risks associated with DNA editing and manipulation.

Boston-based Ascidian will use $50 million in committed Series A funding from ATP to advance its lead program targeting ABCA4 retinopathy and build its pipeline of programs in ophthalmology, neurological and neuromuscular disorders, and rare diseases.

Romesh Subramanian, PhD, will serve as president and CEO. Subramanian joins Ascidian from Dyne Therapeutics, which he founded, and served as CSO and CEO. Prior to Dyne, he co-founded Translate Bio (formerly RaNA Therapeutics), which was acquired last year by Sanofi.

“With RNA exon editing, we can address genes too large to package into a viral vector as well as genes with high mutational variance, which are all currently beyond the reach of gene editing and base editing approaches,” notes Subramanian. “Ascidian’s approach also does not require the use of exogenous enzymes which reduces the risk of immunological response.”

Ascidian’s RNA exon editing platform relies on novel RNA exon editor molecules. A single RNA exon editing molecule can be used to replace multiple mutated exons simultaneously via RNA trans-splicing, without modifying DNA or requiring introduction of exogenous enzymes. Ascidian’s exon editing limits the risk, they say, of off-target DNA edits and expression of transgenes in inappropriate cell types.

Ascidian’s approach to rewriting RNA is mediated by pre-mRNA trans-splicing, a process in which two distinct RNA molecules are precisely linked to form a single mature mRNA sequence. RNA trans-splicing is a phenomenon observed in multiple organisms, including ascidians—ancient ancestors of vertebrates—which deploy trans-splicing to re-engineer their transcriptome.

Ascidian harnesses the RNA splicing machinery of the cell and combines it with large-scale DNA and RNA synthesis, deep sequencing technologies, and clinically validated therapeutic delivery systems, to restore normal protein function.

IND-enabling activities are currently under way for Ascidian’s lead program targeting ABCA4 for the treatment of ABCA4 retinopathy, including Stargardt disease. Stargardt disease is the most common form of inherited macular degeneration and affects approximately 30,000 individuals in the United States. Stargardt disease is caused by mutations in the ABCA4 gene which lead to progressive retinal degeneration and vision loss, typically beginning in childhood and young adulthood.

More than 900 mutations across the ABCA4 gene have been found to cause Stargardt disease. These mutations result in varying degrees of protein expression and disease severity. Diseases caused by ABCA4 loss of function represent an area of significant unmet need that cannot be addressed by standard gene replacement, given the large size of the gene, nor by base editing, due to the high mutational variance of the affected gene.

Ascidian’s RNA exon editing excises disease-causing exons and replaces them with wild-type exons in a single reaction to treat the disease. Ascidian presented data earlier this year at the 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) showing that sub-retinal administration of an AAV-packaged ABCA4 exon editor in non-human primates resulted in successful RNA exon editing as assessed by expression of full-length ABCA4 protein.

In parallel to moving this lead program toward the clinic, Ascidian has successfully demonstrated in vitro exon editing across multiple additional genes and is advancing programs in ophthalmology, neurological and neuromuscular disorders, and rare diseases.

Previous articleZinc May Aid in Rare Genetic Disorder Treatment
Next articleMathematical Model Predicts Risk of Aneurysm Rupture