For years, scientists had known about the myriad ways NLRP3 pushes the innate immune system to go overboard and trigger autoimmune or inflammatory diseases. But until Hao Wu and her Harvard lab came along, nobody really had a good idea of what the protein looks like.
Like other inflammasomes, NLRP3 tends to clump together in vitro, shielding its shape from researchers. Wu’s team — comprising some of the best structural biologists in the world — combined some new protein engineering with the cryo-electron microscopy techniques they know well to crack the problem.
“It’s really satisfying that we got an answer,” Wu said last June, when the finding was published in Nature. “I feel like this means that it doesn’t matter how difficult a problem is; if you put in enough effort, you’ll get it.”
And they didn’t stop at that. The group has elucidated the structures of over 10 more inflammasomes and nucleic acid-sensing targets, and Versant Ventures is now drawing the curtain from Ventus Therapeutics, the biotech startup tasked with bringing forward small molecule drugs against these targets.
Eighteen months after the seasoned team at the Montreal branch of its Inception Discovery Engine started hammering away, Versant has brought in GV to complete a $60 million Series A.
“We have been looking for knowledgeable investors who understand and appreciate the science behind the new innate immune targets,” Wu told Endpoints News in an email. “Versant, especially Jerel Davis, is visionary in this regard.”
Hao Wu (Boston Children’s Hospital)
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With some of the previous programs — most recently at Jecure Therapeutics, whose preclinical pipeline was quickly snapped up by Roche — the VC firm has learned first hand how challenging these targets could be, Davis said. Given the elusive molecular structures and the lack of biochemical or biophysical assays, “in some ways we’re in the 1980s or 1990s with respect to how we did drug discovery on these targets.”
How big of a help turning the lights on in the development process, as CEO Marcelo Bigal compared Ventus’ approach to, remains to be seen.
“Oftentimes it’s a nice-to-have but it’s not necessarily a must-have,” Gary Glick, who founded IFM Therapeutics to pursue a broad range of inflammasomes and nucleic acid sensing targets, said. “Inflammasomes in particular, which are large multi-protein complexes, one could argue there’s debate on how much you need the structure versus how much you may not need the structure.”
That said, he acknowledged that knowing the binding site of a particular molecule can facilitate optimization, understand selectivity of potential drug candidates and shed light on the mechanism. Wu is also an “extremely nice person and an extremely good scientist” from his few interactions with her, he added.
Importantly, Bigal stressed, Wu’s breakthrough wasn’t just about unearthing the structures. It’s also about expressing, purifying and stabilizing the proteins for drug screens.
“It’s pure art,” he said. “For each of them, it’s a different recipe.”
The applications can be broad, capturing everything from genetic diseases to NASH. Within autoimmune and inflammatory diseases, where you’d want to tamp down the innate immunity, it can span certain neurodegenerative disorders, asthma and conditions triggered by infections; in some cases you might want to crank signaling up to attack cancer.
Wu’s protégé Feng Shao has joined her as a co-founder, filling a lineup of prominent academic investigators who are serving as advisors: Yale immunologist Richard Flavell; Judy Lieberman of Harvard, who studies immune pathways that trigger cell death; Thomas Tuschl of Rockefeller, a pioneer in nucleic acid biology; Douglas Green, a co-lead of the cancer biology program at St. Jude Children’s Research Hospital; and Russell Vance at UC Berkeley, whose work on NLRP1 was highlighted.
For now, Ventus has zeroed in on three programs to prioritize initially.
“In due course targets declare themselves,” he said, citing years of drug development experience, including a stint leading R&D at Teva. “What the platform allows us is to get targets at our disposal.”
Work is well underway at Ventus’ labs in Montreal and Boston, where scientists are working in shifts and stay 10 feet apart. Cognizant of both the fears and the sense of mission that the coronavirus crisis is instilling in his scientists, Bigal has started a ritual to meet every Monday to share as a group. And he makes sure the team, which is set to grow past 30 by the end of the year, jumps on a virtual happy hour every Friday.
“It’s actually quite remarkable how much progress some of our preclinical companies are making despite Covid,” Davis said.
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'It's pure art': Versant, GV reveal $60M bet that a clearer look at inflammasomes can lead to better drugs - Endpoints News
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