Nicole Paulk, PhD, emerges from stealth to unveil her Bay area start-up that integrates AAV gene therapy with cytokine immunotherapy to reimagine the elimination of tumor cells and the induction of anti-tumor immunity
Everyone who knows her assumes that Nicole Paulk, PhD, has been working on improvements to the adeno-associated virus (AAV) platform for the past few years. They’re not wrong, but she’s also been working on a secret project that is at last being unveiled at the annual American Society of Gene and Cell Therapy (ASGCT) conference, being held this week in Los Angeles.
Paulk is excited to be launching her company called Siren Biotechnology, which combines AAV gene therapy and cytokine immunotherapy into a single transformative modality.
“Not only is the company coming out of stealth, but we have never talked about this project externally!” Paulk briefed GEN Edge. “We have never presented this at any conference and have never written a grant or a paper about it.”
With participation from Innovation Endeavors, TechBio-focused ARTIS Ventures, Civilization Ventures, and Savantus Ventures, Founders Fund and Lux Capital led Siren’s initial funding. Located in Mission Bay, across the street from Paulk’s former lab at the University of California, San Francisco (UCSF), Siren is looking to grow from its current workforce of eight people.
“It’s white space. There’s never been an AAV in oncology or even an AAV that can be used to treat more than one thing,” said Paulk, who serves as Siren’s founder and CEO. “We’re not limited to only a specific cancer type, primary origin organ, or tissue. This could potentially be the Keytruda of gene therapy. We make it once, and we just use it ‘ten ways to Sunday’ on every potential cancer, both in the monotherapy setting and as a combination therapy with other modalities.”
While Siren will be starting off in oncology because the need is high and the clinical endpoints are clear, Paulk said that the company’s technology is not limited to cancer and can be used in infectious disease, autoimmunity, and longevity.
At ASGCT this week, Paulk will present a talk titled, “AAV Immuno-Gene Therapy Delivers Vectorized Cytokines to Effectively Treat High-Grade Gliomas” on Wednesday afternoon. This will be the first time Paulk shows her foundational work for universal AAV immuno-gene therapies.
Paulk has been working with AAVs for some 17 years. Her “love” for microbes began as an enthusiastic microbiology undergraduate. During her gap year before entering graduate school at Oregon Health & Science University (OHSU), she answered a local Craigslist ad to become a technician, cleaning dishware, autoclaving, and performing simple lab tasks. The position was in the lab of Markus Grompe, MD, an OHSU professor who had made a name for himself in gene therapy circles by creating a transgenic mouse model of a metabolic disorder called Type I tyrosinemia.
Paulk started assisting graduate students and postdocs in Grompe’s lab and became enamored with the use of AAVs as a tool to label cells, “turning them green and making them do things.” She was magnetized by a project making liver gene therapies and was set on working with viruses when starting graduate school.
“This was still when gene therapy was exceptionally unpopular,” said Paulk. “There was no getting an NIH grant or running a clinical trial. This was still like the dark ages, but I was just fascinated by the possibility of engineering these viruses as FedEx trucks delivered medical packages throughout the body. This just sounded cool to me.”
For Paulk, the unpopularity of gene therapy at the time—still recovering from the death of Jess Gelsinger in 1999—was a blessing. “There was all this foundational work that needed to get done, and no one was working on it. Absolutely no one wanted to be in that field because no one would publish your story. So, there was all this groundwork that needed to be laid.”
Paulk stayed on in Grompe’s lab for her graduate work, and after publishing six papers in three years, headed to Stanford for a postdoc. Around this time, while gene therapy was still unpopular, the tide was starting to turn with the emergence of the Luxturna data, which lured venture capitalists into sniffing around conferences like ASGCT.
“Folks with suits started to show up at ASGCT. It felt like something was in the air— something’s changing,” said Paulk. “Within 2–3 years into my postdoc, that’s when it hit. All you heard about was gene therapy. It was everywhere, and it was all anybody was talking about.”
By the time Paulk had finished her postdoc and joined the faculty at UCSF, gene therapy had caught fire. And while people started to pivot towards gene therapy from genomics and other nearby fields, Paulk was already set to ignite.
All for one, and one for all
After launching her own lab in 2017, Paulk began whiteboarding some of the biggest challenges in gene therapy that had to be answered in academia (due to the risk). In addition to wanting to stay away from the same few genetic indications that have garnered a lot of attraction in these early days of gene therapy, Paulk kept returning to the fact that every gene therapy is personalized.
“Each program is bespoke for an indication,” Paulk told GEN Edge. “You can’t treat a little boy with hemophilia B with the AAV you made for a little girl with spinal muscular atrophy. Because each program is built from scratch, often several years apart, there aren’t the economies of scale that you get with a small molecule. So, we set out to make what we were calling ‘universal gene therapy.’”
A universal AAV that could be used to treat multiple indications, whether rare or common, has the potential to shave the amount of clinical development time and capital needed to advance any program.
Behind this concept, Paulk began to think about payloads that weren’t limited to single monogenic disorders and that modulate cell signaling, interactions, and states. She eventually landed on cytokines.
“We wanted to branch out into payloads that are much more modular and broader in their effect,” said Paulk. “To create a gene therapy that can be used to treat thousands of indications, we needed payloads that weren’t restricted to a single disease class. We really started getting excited about cytokine payloads because of the broad number of cell types that they talk to, the number of tissues for which there are receptors, and the fact that your body already naturally uses this to communicate things to itself.”
And that’s when the thunderbolt struck: could AAV delivery be used in oncology?
On paper, AAVs don’t appear to have much use in oncology because they’re not oncolytic, they don’t replicate or lyse host cells, and they don’t travel between cells. In the same manner as the Montagues and Capulets, oncologists and AAV gene therapists don’t talk much because the fields don’t overlap, according to Paulk. But the big problem with cytokine immunotherapies for oncology is that their half-life lasts on the order of minutes or hours, even when enveloped in nanoparticles or ornamented with a biochemical substance.
As the bread and butter of AAV gene therapy is cDNA expression, Paulk saw a huge opportunity to extend cytokine half-life by leveraging the durability, cloaking, and targeting aspects of gene therapy.
The innovations at Siren aren’t necessarily based on the fundamental core biology components of the virus. The capsid and normal genome configuration have been untouched. What Paulk has done at Siren is to try to perfect cytokine payloads instead of delivering cDNA that codes for a gene that’s missing or mutated in a monogenic disease.
So, Paulk jumped into the deep end. Nearly six years later, she resurfaced with Siren Biotechnologies with the vision for universal AAV immuno-gene therapy to become the standard of care for any solid tumor cancer.
At ASGCT, Paulk will present experiments conducted by Siren’s founding scientists to evaluate the safety and efficacy of an immuno-gene therapy that utilizes AAV9 vectors expressing a dozen engineered immunomodulatory interferon (IFN) cytokine payloads comprising IFNɑ1, IFNβ, IFNƔ, and combinations thereof. Bolstered by the initial results, Paulk said that Siren’s journey will commence with an initial focus on brain and eye cancers, which have been elusive for treatment with system drugs.
“Siren, and a few other companies, are leading the pack on second-generation gene therapy technologies that are not using all the [original] methodologies and going after the same six indications that everyone’s going after,” said Paulk. “As we expand into a bigger indication space, it’s going to be really exciting.”
This story was first published in GenEngNews. Read it here: https://www.genengnews.com/gen-edge/asgct-news-siren-biotechnology-hails-universal-gene-therapy-for-oncology/