Science
Ascidian's Approach

Rewriting RNA – Ascidian’s exon editing platform

Expanding the therapeutic possibilities of RNA medicine for patients

The transcription of DNA into RNA is a fundamental biological process.

During transcription, cellular machinery transcribes a gene’s introns and exons into a pre-mRNA molecule. Then, during the process of RNA splicing, introns are removed and exons are spliced together to form mature mRNA that is translated into protein. Mutations anywhere in these exons may result in malformed proteins, often causing severe disease.

What if we could identify and correct these mutations to slow, stop, or even reverse disease?

The large size and high mutational variance of many genes places them beyond the reach of existing gene editing and base editing approaches.

Ascidian Therapeutics is taking a fundamentally different approach by editing exons at the RNA level

RNA exon editing produces mRNA levels consistent with intact gene expression circuitry

By replacing mutated exons, 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 sharply reducing risks associated with DNA editing and manipulation.

Exon editing explained

Ascidian's first-of-its-kind RNA exon editing platform deploys high-throughput molecular biology in tandem with cutting-edge computational biology to design novel RNA exon editor molecules.

A single exon editing molecule can be used to replace multiple mutated exons simultaneously through pre-mRNA trans-splicing, without modifying DNA and without requiring the introduction of foreign enzymes. Ascidian’s exon editing takes place at the RNA level, thereby limiting risk of off-target DNA edits or expression of transgenes in inappropriate cell types.

RNA exon editing excises mutated exons and replaces them with wild-type exons in a single reaction to restore normal protein production

Since only disease-causing exons in a gene need to be replaced, the exon editing molecule is small enough to fit in AAV or other viral or non-viral delivery vehicles, including lipid nanoparticles. Ascidian’s platform is versatile, allowing the RNA exon editing therapeutics to be administered using a delivery vehicle targeted specifically to the location where post-transcriptional editing is needed to treat disease.

RNA Exon Editing vs Gene Editing

RNA exon editing is designed to provide the durability and benefits of gene therapy, without the risks associated with direct DNA editing or gene replacement.

Edits RNA, not DNA

Edits RNA, not DNA:

Reduces risks associated with genomic modifications

Edits whole exons at the kilobase scale, not only single bases

Edits whole exons at the kilobase scale, not only single bases:

Precisely corrects multiple whole exons, which can address more mutations to treat more patients than current gene editing or base editing approaches

No foreign enzymes

No foreign enzymes:

Does not require exogenous or foreign enzymes (e.g., bacterial enzymes), which can pose immunological risks or require delivery with dual AAV vectors

Maintains native gene expression

Maintains native gene expression:

Ensures target gene expression is precisely controlled by the cell

Agnostic to delivery vehicle

Agnostic to delivery vehicle:

Overcomes packaging capacity limitations of delivery vectors such as AAV, and can be used with multiple, clinically validated delivery vehicles – viral and non-viral – tailored appropriately for each program; delivered as a single construct

The next wave of RNA therapeutics

Ascidian’s RNA exon editing platform is designed to expand the potential of RNA medicines for patients and their families who are seeking breakthroughs.

Ascidian is developing a broad pipeline to impact significant diseases that cannot be addressed with existing technologies. Our lead program targets ABCA4 retinopathy, including Stargardt disease, the most common form of inherited macular degeneration.

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