Just before noon on May 17 at the American Society for Gene and Cell Therapy’s annual meeting, a young, buzzing crowd filled a small conference room at the Los Angeles Convention Center for a special lunch session. Snapshots of the host company’s staff embarking on outdoor adventures rolled across the projector screen to the tune of upbeat pop music blaring from loudspeakers.
One might be tempted to conclude that the group was drawn in by the promise of free wraps and croissants. But that alone couldn’t explain it: After all, right downstairs, CRISPR pioneer Jennifer Doudna, Ph.D., Harvard chemist David Liu and a handful more of the field’s most lauded scientists were giving the conference’s keynote speeches. That roster had enough star power to lure in even the most die-hard free food connoisseurs.
No, this crowd had been called not by sandwiches but by something more powerful: The song of Siren Biotechnology, a brand-new startup that’s merging immunotherapy and gene therapy to build a platform of universal adeno-associated viruses, or AAVs, to treat brain and eye cancers—and eventually, much more. Siren had just that morning emerged from stealth mode. Now, its vivacious founder and CEO Nicole Paulk, Ph.D., a rising star in her own right (and already Twitter-famous in the gene therapy space), was laying out her big vision to potential recruits.
“We wanted to ask a pretty bold question: What if there were no limits to AAV gene therapy?” she told her audience. “What if you could have a universal AAV that could be used to treat 20 things or two hundred things? What would that change?”
Siren is a spinout of Paulk’s lab at the University of California, San Francisco, where until 3 a.m. on May 17 she was an assistant professor. Her team started out developing an AAV vector that could express universal payloads—transcription factors, cytokines, chaperone proteins and other things that could potentially take the use of AAVs beyond rare, monogenic disease. Then, researchers from the university’s clinical cancer center caught word of her work.
“They came to us and said, ‘Can you use some of these in an oncology setting?’” Paulk told Fierce Biotech in an interview. “We thought, ‘Gosh, that’s a really good idea. We should collaborate.’”
Normally, gene therapists “play in the rare monogenic mendelian disorder sandbox,” as Paulk put it, which so far has been the main use for AAVs. They aren’t yet common in oncology; the only therapy that’s similar to what Siren is attempting to build is Ferring Pharmaceuticals’ Adstiladrin, indicated for the treatment of bladder cancer. That one uses an actual adenovirus vector, which is different from an AAV.
Some of the fundamental biological characteristics of AAVs that made them challenging to use in gene therapy make them ideal for use in immuno-oncology, Paulk added. They’re known to be “sticky,” for instance, latching themselves onto labware and off-target tissues alike. While that can make them hard to work with some in gene therapy applications, it’s a boon when it comes to cancer, she said.
“If you’re delivering these AAVs locally within tumors, they will stay exactly where you put them, so you get this very precise, direct intratumoral delivery of these AAVs,” she explained. On top of that, AAVs have a steady, long-term expression. This makes up for the short half-life of cytokines, which is one of the reasons they still aren’t commonly used in cancer despite years of trying, Paulk added.
The team set its sights on eye and brain cancer to start, in part because the sites are already well-studied in gene therapy. They’re also immune privileged, meaning they’re cordoned off from the systemic immune system and have their own. That makes it less likely that a patient would have pre-existing antibodies to AAVs, which is the case in somewhere between 30% and 60% of individuals.
Paulk released some of Siren’s latest preclinical data in a separate presentation at ASGCT. The researchers developed AAV vectors that expressed 12 cytokine payloads, among them interferon alpha 1, interferon beta, interferon gamma or a combination of the three. They then tested them in human cerebellar organoids and mouse models of aggressive high-grade glioma, including a group of mice that had been grafted with tumor cells from human patients. They compared the AAVs’ performance to that of the glioma chemotherapy temozolomide.
The treatment outperformed temozolomide in both cases, both in terms of toxicity and in killing off tumor cells. The AAVs also increased survival in the mice (450 of which were treated with one of the AAVs). Depending on the mouse model and the type of AAV used, they saw a complete response in somewhere between 31 and 60% of cases.
Why hasn’t an AAV-based gene-immunotherapy been tried before? According to Paulk, it was communication barriers—not technical ones—that kept the two apart.
“It’s like oil and water. [Immuno-oncology and gene therapy] are just these two worlds that have never talked to each other,” Paulk said. “That dream of taking things from bench to bedside, of interdisciplinary science—it’s actually really hard to pull off because these are groups that don’t often get the opportunity to really get into the weeds together.”
Siren is in the process of raising funds to close its series A. So far, Founders Fund, Lux, Artis Ventures, Innovation Endeavors and Civilization Ventures have all pledged their support. Despite being a new idea, Siren’s concept isn’t being met with much skepticism, Paulk said. Investors are excited about the white space and that the company is far enough ahead in its product development that it may be able to outrun the classic “fast follower.” The biggest hurdle is getting investors to feel comfortable again with the word “platform.”
“‘Platform’ is a bad word now—it’s something that has fallen out of favor,” she said. “But it has to do normally with technology platforms, not therapeutic platforms, which is a completely different space.”
Editor's Note: An earlier version of this article misspelled Civilization Ventures. The name has been corrected.