While studying at the U, she researched total synthesis of natural products in Gary Keck’s lab and played on an intramural soccer team where she met her husband.

Wager is a chemistry midfielder in her career, driven to cover a lot of ground by her passion for working in a fast-paced, team environment. After graduating from the U, she spent 17 years at Pfizer as Senior Principal Scientist, Director of Business Planning, Chief of Staff for Pfizer Medical, and Medical Strategy Lead in Oncology. Then she earned her MBA from MIT in 2017 before joining Ascidian Therapeutics. “I really found the place where my heart belongs, and that’s working in startups,” she says. “In those situations, it’s pretty high risk, but also high reward. The strength of the team is critical, and I really enjoy that part. I’ve always been into team sports. I love having a phenomenal team that I work with.”


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.

No Magic Bullet

While RNA exon editing is an exciting new strategy for tackling genetic disease, that’s not to say that other tools like CRISPRCas9 aren’t useful. “I’ve been in drug discovery for twenty-three years now,” says Wager. “I don’t think that there is one type of way to ameliorate disease. [T]here’s lots of different ways. They all have their niche.”

In this way, the multi-faceted dynamic of the fight against genetic diseases mirrors that of the startup culture where Wager excels. “When you find a place where it’s not just that you enjoy what you’re doing, but you thrive, that’s what the startup environment for me is [with] super intelligent people [who are] super motivated to make a difference in patients’ lives.”

Each scientist brings something different to the startup, and Wager’s expertise along with her technical skills which she attributes to her time at the U makes her a valuable addition to the team. Through her training she “learned how to exquisitely design and execute research problems in this [startup] environment… .”

“I truly believe that my graduate training here [the U] has set me up to be able to do whatever I want. … I’ve had a bunch of twists and turns [in] my career… I didn’t stay in one kind of role for more than five years. The U just teaches you skills that carry over in everyday life and in your career, and I really am grateful for how we were set up [early] to do research.”

The extensive application of Wager’s education is a testament to the quality of the chemistry department’s graduate program, successfully preparing students for careers in academia, industry, and beyond. The Distinguished Alumni Award celebrates Wager’s impressive career since her time at the U, but really, she’s just getting started in her match against genetic disease. <

By Lauren Wigod