Alnylam founding CEO launches new RNAi start-up

When Alnylam Pharmaceuticals founding CEO John Maraganore left the company in late 2021, he joked that he wanted to be a “grandfather” of biotech—not leading any companies, per se, but guiding them along by taking advisory and board seats.

That course has changed slightly. On Tuesday, Maraganore launched a start-up, City Therapeutics, that builds on his 20-year career at Alnylam by making smaller versions of the RNA molecules that silence genes to treat diseases.

Maraganore is partial to RNA interference (RNAi) as a drug mechanism; in 2018, Alnylam became the first company to have an RNAi drug approved by the US Food and Drug Administration. So in the summer of 2023, when he came across a paper from chemist Kotaro Nakanishi at the Ohio State University, he was intrigued. Nakanishi and his colleagues had found that certain, tiny RNA molecules could activate the protein Argonaute3 to slice through proteins (Proc. Natl. Acad. Sci. U.S.A. 2020, DOI: 10.1073/pnas.2015026117). They called the molecules cleavage-inducing tiny guide RNAs, or “cityRNAs.” A seed was planted: use those minuscule RNAs to get to tissues that large molecules—like traditional small interfering RNA—can’t reach.

“Gosh, this is quite interesting,” Maraganore remembers thinking. “I wonder if we can think about novel approaches with these cityRNA molecules.”

Specifically, he wanted to see whether cityRNAs could be used to make drugs that could be delivered outside the liver, a longstanding goal for Maraganore and his colleagues in the field. (In fact, one extrahepatic organ—the kidney—is the focus of Judo Bio, another RNAi start-up that launched this week and counts Maraganore among its advisers.) Maraganore reached out to friends at Arch Venture Partners and began building City Therapeutics around a year ago. Stat News first reported on City’s launch.

Maraganore sees potential for cityRNAs to help silence disease-causing genes in multiple target tissues, including the central nervous system, the eye, muscle, adipose or fat tissue, the lung, and tumors.

The 30-person City Therapeutics is currently without a CEO, so Maraganore is taking on some operational responsibilities, though he eschews the title. Formally, he is chairman of the firm’s board. Former RTW Investments principal Sebastian Trousil is the start-up’s chief operating officer, while Tracy Zimmerman, a veteran of Generation Bio and Alnylam, serves as chief scientific officer.

City expects to start testing its first drug candidate in humans by early 2026 with the help of a $135 million series A financing led by Arch. Maraganore envisions one to two clinical trials for new drug candidates beginning each year starting around 2026.

“It’s a big world of unmet need,” he says.