With $50 million in backing from Apple Tree Partners, Ascidian Therapeutics launches Tuesday with technology that allows for the treatment of some diseases through rewriting of RNA.
Ascidian CEO Romesh Subramanian, Ph.D./courtesy of Ascidian Therapeutics
With $50 million in backing from Apple Tree Partners, Ascidian Therapeutics launched Wednesday with technology that allows for the treatment of some diseases through rewriting of RNA, a new therapeutic class of medicines.
Boston-based Ascidian will use the Series A financing to advance its lead therapeutic program that targets ABCA4 retinopathy, which includes Stargardt disease, the most common form of inherited macular degeneration. Unlike gene therapies that target DNA, Ascidian’s approach edits the disease-causing exons and replaces them with wild-type exons.
Ascidian CEO Romesh Subramanian, Ph.D., a longtime expert in the field of RNA and founder of Dyne Therapeutics, likened Ascidian’s approach to editing a book rife with errors following publication. Imagine opening a book that has been published and finding spelling and grammatical errors throughout, he said. Instead of correcting each mistake manually, Subramanian said, a more efficient way would be to precisely fix whole chapters of the book.
“That’s what we can do with disease. What we essentially do is use RNA to splice in and replace mutated exons with wild-type exons. If there are multiple mutations we can drop in a large set of exons and correct it,” Subramanian told BioSpace.
A single RNA exon editing molecule is able to be used to simultaneously replace multiple mutated exons through RNA trans-splicing, Subramanian said. This approach can be done without modifying DNA or requiring the introduction of exogenous enzymes, maintaining native gene expression patterns and levels.
Ascidian’s approach is designed to provide the durability of gene therapy already established by other therapeutics, such as Spark’s Luxturna.
At the same time, Ascidian’s program is designed to reduce the known risks associated with DNA editing and manipulation. Subramanian noted that exon editing takes place at the RNA level, which limits the risk of off-target DNA edits and the expression of transgenes in inappropriate cell types.
Looking at the first indication the company is targeting, Subramanian said conventional gene therapy approaches could not address this disease since the replacement process is too large to put into a conventional vector.
Instead, Ascidian designed an RNA construct that is delivered into the nucleus of the cells in the eye. This, in turn, harnesses the cells’ machinery to put the replaced exons in the right spot.
“This is a phenomenal technology,” said Subramanian, who spent years studying different therapeutic approaches, including nucleic acid, antibody and enzyme replacement therapies.
Michael Ehlers, chief scientific officer and partner at ATP, who was the founding CEO of Ascidian, said the company’s approach is a retooling of previous attempts at RNA trans-splicing, which had largely been abandoned due to low efficacy. He noted that, as far as he was aware, no other company is working on a similar therapeutic approach now.
Relying on high-throughput molecular biology and computational biology, Ascidian is able to harness RNA splicing machinery of the cell and combine it with large-scale DNA and RNA synthesis, sequencing technologies and clinically validated therapeutic delivery systems. This is done to restore normal protein function and improve the patient’s life.
“In essence, we found an old gem and polished it up, one that had been long neglected,” said Ehlers, who transitions into the role of chairman of the Ascidian Board of Directors. “We can change thousands of bases at a time. By rewriting RNA, Ascidian has the potential to fundamentally transform the fields of RNA therapeutics and gene editing by addressing the underlying causes of disease.”
As Ascidian emerges from stealth mode, the company is already eying the filing of an Investigational New Drug application for its lead program. Ehlers and Subramanian both noted that Stargardt disease is an appropriate indication to showcase the capabilities of Ascidian’s technology.
More than 900 mutations across the ABCA4 gene have been found to cause Stargardt disease. Data in non-human primate studies presented earlier this year at the 25th Annual Meeting of the American Society of Gene and Cell Therapy demonstrated successful RNA exon editing following sub-retinal administration of the company’s therapeutic, as assessed by expression of full-length ABCA4 protein.
In addition to its ophthalmology program, Ascidian, which has about 30 employees at the moment, is also advancing preclinical programs in neuromuscular disorders and rare diseases.
“We’re generating data on other targets and making good progress on IND-enabling studies,” Ehlers said.
