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Start-ups

Two siRNA firms launch

Judo Bio and City Therapeutics both want to go after tricky tissues

by Rowan Walrath
October 11, 2024 | A version of this story appeared in Volume 102, Issue 32

One scientist looks into a microscope while another observes. Both are wearing lab coats, black nitrile gloves, and safety glasses.
Credit: Judo Bio
Scientists work in the Judo Bio laboratory.

Two start-ups have launched to develop next-generation drugs using small interfering RNA (siRNA) to silence genes.

The first, Judo Bio, is a spin-off of the venture capital firm Atlas Venture. The company spent about 3 years in stealth while designing a drug candidate that combines a ligand with siRNAthat should silence messenger RNA (mRNA) and, in turn, reduce the number of certain solute carrier proteins that are involved in disease.

While siRNA is a proven therapeutic approach, getting it to the right cell types is challenging. The kidney is a “very complex tissue,” says Chief Scientific Officer Alfica Sehgal, a former head scientist at RNA biotech firms Camp4 Therapeutics and Alnylam Pharmaceuticals. The organ consists of multiple tissue types, making specificity difficult. The glomerulus, a network of blood vessels in the kidney, also filters out molecules by size; it excretes siRNA by default.

“It’s not an easy bean to crack,” Sehgal says.

But Judo Bio has proposed an elegant solution. The ligand acts as a hook on the siRNA so that, on its way out, the conjugate latches on to the kidney’s proximal tubule epithelial cells via a receptor called megalin. From that perch, the siRNA can act on the mRNA.

The start-up recently closed a series A investment round that, when combined with its seed funding, comes out to $100 million. Atlas, the Column Group, and Droia Ventures co-led the series A.

While Judo Bio was preparing for its public launch, so was another siRNA start-up. City Therapeutics, the latest project of Alnylam founding CEO John Maraganore, debuted the day after Judo Bio did, following about a year in stealth.

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 Maraganore 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 protein argonaute-3 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 siRNA—can’t reach.

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. He expects City will start testing its first drug candidate in humans by early 2026 with the help of a $135 million series A financing round led by Arch Venture Partners. 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.

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