RARE Daily

Ascidian Therapeutics Launches to Rewrite RNA

October 12, 2022

Ascidian Therapeutics, a biotechnology company built and developed by venture capital firm ATP and funded with a $50 million in a series A financing, launched with a focus on treating human diseases by replacing mutated exons at the RNA level.

Photo: Romesh Subramanian, president and CEO of Ascidian

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. Ascidian is advancing its lead program for ABCA4 retinopathy in IND-enabling studies while it progresses its pipeline of programs in ophthalmology, and neurological, neuromuscular, and rare diseases.

Romesh Subramanian, formerly founder and CEO of Dyne Therapeutics, is Ascidian’s president and CEO. Michael Ehlers, chief scientific officer and venture partner at ATP, and founding CEO of Ascidian, will become chair of Ascidian’s Board of Directors.

“Ascidian has the capability to redefine the treatment of genetic diseases by editing exons at the RNA level,” Subramanian said. “Using this approach, we can replace genes too large to package into a viral vector as well as genes with high mutational variance, all of which are currently beyond the reach of gene and base editing approaches.”

Ascidian’s platform deploys high-throughput molecular biology in tandem with cutting-edge computational biology. A single Ascidian RNA editor can replace multiple mutated exons simultaneously, without modifying DNA, thereby limiting the risk of off-target DNA edits and expression of transgenes in off-target cell types. Moreover, the technology does not require the introduction of exogenous enzymes, reducing the risk of immunogenicity.

“ATP built Ascidian 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.

Ascidian’s technology is based on RNA trans-splicing, a phenomenon observed in multiple organisms, including ascidians—ancient ancestors of vertebrates—which deploy trans-splicing to re-engineer their transcriptome. As applied by Ascidian, RNA trans-splicing enables excision of disease-causing exons and their replacement with wild-type exons in a single reaction to treat disease.

IND-enabling activities are under way for Ascidian’s lead program targeting 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 alone. Stargardt disease is caused by mutations in the ABCA4 gene which can 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 that cause Stargardt disease. These mutations result in varying degrees of protein expression and disease severity. Diseases caused by ABCA4 loss of function are examples of genetic disorders that cannot be addressed by standard gene replacement, given the large size of the gene, or by base editing, due to the high mutational variance of the affected gene.

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 one of its ABCA4 exon editors resulted in expression of full-length ABCA4 protein in non-human primates.

The company has also demonstrated excision and replacement of mutated RNA exons with wild-type RNA sequences in multiple genes and cell types, and is advancing programs in ophthalmology, and neurological, neuromuscular, and rare diseases in preclinical studies.

Author: Rare Daily Staff    

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