Two and a half years ago, Nicole Paulk’s coworkers told her to start a company. The gene therapy researcher and then University of California, San Francisco assistant professor had just showed them data from mice studies testing a new kind of cancer treatment her lab was developing, and they were impressed.
The presentation was internal, to physicians and researchers, but the positive feedback led Paulk to visit the university’s entrepreneurship center the same day.
“That was how it started,” said Paulk. “We had no thoughts of spinning this out, and our clinical colleagues were the ones who convinced us that this merits some venture capital dollars.”
On Wednesday, after keeping her company secret since that late 2020 meeting, Paulk is revealing the startup she formed. Called Siren Biotechnology, it’s melding two distinct research fields: gene therapy and cancer immunotherapy.
Paulk, who’s left her position at UCSF to become Siren’s CEO, will on Wednesday also present the latest preclinical research supporting her company’s approach at the American Society of Gene & Cell Therapy’s annual meeting. The results include more data showing Siren’s treatment can shrink a type of brain tumor in mice.
Siren aims to use adeno-associated viruses, or AAVs, to deliver into tumors engineered versions of small signaling proteins called cytokines. These proteins are part of the body’s immune defense against threats like cancer and some, like interferon-alpha and a cytokine called IL-2, have been studied for years as cancer treatments.
But using cytokines as therapy has drawbacks that have stymied other efforts. Chiefly, cytokines don’t last long in the body, forcing drug researchers to try higher doses that come with greater side effects.

“We saw this as a huge opportunity because this is our bread and butter in the AAV gene therapy field. We express things forever,” said Paulk.
For rare genetic disorders, researchers can package functional copies of genes that are missing or broken into AAVs and, by shuttling them into the right cells, overwrite the underlying cause of disease for many years. Using AAVs to deliver DNA encoding for the right cytokines could similarly offer a way to more durably deliver the immune-stimulating proteins.
Additionally, because AAVs generally don’t integrate into the DNA of a cell, Paulk anticipates that Siren’s “immuno-gene therapy” will be self-limiting.
“[AAV expression] has been a challenge in the rare disease space, where we're trying to express something forever in a tissue that either turns over or in children who are growing,” she said. “But it's a huge advantage in oncology because now we can deliver a functional copy of a cytokine and it will last exactly as long as we need it to — only as long as the tumor is alive.”
Some precedent exists for what Siren plans to do. In December, the Food and Drug Administration approved a drug from Ferring Pharmaceuticals that uses a different virus to deliver a copy of the gene that encodes for interferon-alfa 2b. It’s cleared to treat a type of bladder cancer.
Siren claims it’s the first to be developing an AAV gene therapy for cancer. The company will target cancers of the brain and eye, where its cytokine-encoding AAVs can be injected directly into tumors. The company also pitches its approach as “universal,” meaning the same treatment design could be used against many types of brain cancer, for example.
According to Paulk, this will be an advantage for Siren, which won’t have to redesign the viral shell and the payload it delivers for each type of tumor — different than in rare disease, where AAV gene therapies are customized for each specific condition.
“Everything stays the same, so you can take that [clinical trial application] and copy, paste, find, replace,” said Paulk. “Now you can leverage the safety data across these trials and have them point to each other because every aspect of the trial is the same other than the origin tumor.”
This vision of a multi-purpose gene therapy was where Paulk and her colleagues originally started four years ago, brainstorming the limitations of the technology on a white board. The biggest stumbling block they identified was the costly and time-consuming process of designing a custom gene therapy from scratch for each rare disease.
Exploring gene payloads that could be used to treat multiple conditions led them to cytokines, which gave them the idea of using AAVs in cancer. It’s an odd marriage of technologies that, in Paulk’s view, have been kept apart for the simple reason that researchers in the two fields don’t often overlap.
“Oncologists and AAV gene therapists don’t talk to each other. There is no overlapping conference. There is no academic department that carries both [kinds of] people,” said Paulk.
Siren raised seed funding in September 2021 and is currently working on closing a Series A round. It’s backed by Founders Fund and Lux Capital, among other investors.