Ascidian Therapeutics, a biotechnology company focused on treating human diseases by rewriting RNA, has been launched.
With an initial focus on replacing mutated exons at the RNA level, Ascidian’s technology enables therapeutic targeting of large genes and genes with high mutational variance while maintaining native gene expression patterns and levels. This approach is designed to provide the durability of gene therapy while reducing risks associated with DNA editing and manipulation.
Boston, U.S.-based Ascidian was created in 2020 with $50 million in committed series A funding from ATP to advance its lead program targeting ABCA4 retinopathy and build its growing pipeline of programs in ophthalmology, neurological and neuromuscular disorders, and rare diseases.
Ascidian has appointed Romesh Subramanian, formerly founder and CEO of Dyne Therapeutics, as its president and chief executive officer. After serving as founding CEO, Michael Ehlers, chief scientific officer of ATP and a venture partner at the firm, will become chair of Ascidian’s board of directors.
“I am honored to lead Ascidian as we expand the therapeutic potential of RNA medicine for patients who are awaiting breakthroughs,” Subramanian said.
“Ascidian is redefining the treatment of genetic diseases by editing exons at the RNA level. 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. Ascidian’s approach also does not require the use of exogenous enzymes which reduces the risk of immunological response.”
Ascidian’s first-of-its-kind RNA exon editing platform deploys high-throughput molecular biology in tandem with computational biology to design 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 takes place at the RNA level, thereby limiting risk of off-target DNA edits and expression of transgenes in inappropriate cell types.
‘Transforming RNA therapeutics’
“ATP created Ascidian and has invested to build the company over time, because we believe that rewriting RNA has the potential to fundamentally transform the fields of RNA therapeutics and gene editing by addressing the underlying causes of disease,” Ehlers said.
“We are thrilled to welcome Romesh at this critical time in Ascidian’s growth as we advance our lead program toward the clinic and expand our pipeline with programs in neuroscience and other therapeutic areas, aimed at bringing novel treatments to patients in need.”
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 and transform the treatment of human disease.
Lead program targeting ABCA4 retinopathy
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 U.S.
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.
American Society of Gene and Cell Therapy presentation
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 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 its 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.