EXON-EDITING IS THE NAME OF THE GAME
Carrie Wager
The team Wager currently works with at Ascidian is taking a new approach to gene therapy, influenced by the organisms that the company is named after. Wager says, “We were inspired by what happens with sea squirts or ascidians because they re-engineer the transcriptome. They start as creatures that are free-floating … but then they become these structures after they re-engineer their transcriptome and are fixed on the bottom [of the ocean].” As sea squirts (Ascidiacea) mature, they self-edit their messenger RNA to change the proteins that are expressed and, ultimately, their structure.
Ascidian’s strategy for fixing genetic diseases in humans is different from other existing methods of gene therapy because it works by editing RNA through a process that is already inherent to the cell. “DNA is transcribed into RNA in the nucleus,” Wager explains. “It’s initially transcribed into pre-messenger RNA (pre-mRNA) and pre-mRNA becomes mature RNA, which leaves the nucleus. But the process of going from pre-mRNA to mature RNA is the excision or the cutting out of introns.” The splicesome is the enzyme responsible for removing the introns and leaving the exons which are then joined to form the mature strand of RNA.
Ascidian designs molecules to target mutant exons and replace them with a wild-type version. “We use these molecules that are packaged in an adeno-associated virus to gain entry into the nucleus. Then those molecules are built to bind to specific locations in messenger RNA. … The spliceosome machinery comes along and flips-in our healthy exon that’s packaged in our molecules and removes the mutant components. Then that [corrected RNA] continues on outside of the nucleus into the ribosomes, and you generate the healthy protein.”
The procedure or process can sound convoluted and dicey–like a wellplaced strike by Spain’s Olga Carmona during the final of the recent FIFA Women’s World Cup. But the stakes are just as high (and even higher for its beneficiaries) for Wager and her team whose exon editing method has many advantages over other gene therapies. Since only the RNA is being edited, risks associated with DNA editing are reduced. Harnessing a natural cellular process prevents the need for bacterial enzymes, which pose an immunological threat, to be introduced to the cell.
The most impactful benefit is the amount of editing that can be done at one time. For example, Ascidian is currently focused on addressing Stargardt’s disease, a genetic retinal disease that causes blindness and stems from mutations in the ABCA4 gene which codes for the protein involved in clearing vitamin A from the retina. Without the healthy protein, toxic compounds begin to accumulate in the eye, destroying cells and impairing central vision function.
Rather than doing “point mutations or small base insertion,” Wager uses technology that replaces whole exons. “We can swap out up to 4,000 nucleotides. So that allows you to make a difference in diseases that have really big gene sizes and genes that have high mutational variants. With one drug we can cover the majority of patients.” If Ascidian’s exon editing idea passes human trials and FDA approval, the treatment is something any ophthalmologist could do during a half-day clinic.