Writing the future of genetic medicines, with Stylus

Stylus Medicine, an RA Capital portfolio company developing transformative in vivo genetic medicines, emerged from stealth this week with $85 million in Series A funding. We started Stylus with our friends at Khosla Ventures and a stellar team of academic founders (Patrick Hsu, Ami Bhatt, Michael Bassik, and Lacramioara Bintu) back in 2022, built the company rapidly via our Raven incubator, and we’re thrilled to participate in this recent financing. We are also excited for everyone to see a piece of Stylus’s scientific progress this week when they showcase their preclinical data at the American Society of Gene & Cell Therapy conference.

Stylus is positioned to overcome the existing limitations of genetic medicines with its suite of engineered recombinases that are designed to recognize a safe harbor site in the human genome and introduce a therapeutic payload with high specificity and integrity. Stylus’ initial focus is on developing in vivo CAR‑T therapies that will deliver a recombinase and a DNA construct encoding a chimeric antigen receptor (CAR) payload directly to T cells in a patient’s body via a cell-targeted lipid nanoparticle, turning the patient’s own immune system into an anti-cancer factory. The elegance and scalability of this in vivo nonviral approach will dramatically expand the accessibility of these life-changing therapies, enabling many more patients to benefit.

The right tool for the right job 

RA Capital and Raven NewCos always start with a ​“What if?” statement. Though we love cool new biotechnology (we’re a team of scientists, after all), we don’t let ourselves get seduced by shiny platforms in the absence of a clear application that solves a real problem. Stylus came out of a half-year-long process of systematically assessing the clinical and technological problems of existing genetic medicines that needed to be solved. 

Gene therapies on the market today use adeno-associated virus (AAV), which works well for diseases where the gene is small enough to fit in the viral vector. However, AAV isn’t suitable for delivering large genes, and because the therapeutic gene is not integrated into the genome and does not replicate with the cell, it can get diluted as cells divide, sometimes causing efficacy to decline over time. The pioneering CRISPR companies use their molecular scissors to cut the genome at a certain point and inactivate a bad gene. These changes are permanent and persist as cells divide, but CRISPR can’t easily insert the corrected version of a missing or broken gene. Similarly, platforms like prime and base editing can make permanent, small edits to correct mutations but are not practical for full-length gene insertion. Lentivirus can address this issue, but it integrates the gene into random sites in the genome. This works great for some applications, but delivering the gene to a site in the genome that is known to be safe (i.e., won’t inadvertently break an important gene or introduce a cancer-causing mutation) would be even better. Furthermore, viral vectors like AAV and lentivirus aren’t redosable. The body generates antibodies that would fight off the viral vector if it were given to the patient again. So you only get one shot, which is not ideal if the efficacy fades over time. 

What if we could permanently deliver a corrected or therapeutic gene, ideally in a site in the genome known to be safe, ideally with a nonviral delivery system? There are a number of diseases that are not treatable with existing genetic medicines because of these limitations that such a technology could unlock. Thus began our search.

Stylus origins

Cosmas, an experienced genetic medicine entrepreneur who had previously founded a circular RNA company, had just joined Raven in December 2021 when a friend reached out with news: Cal Berkeley’s Patrick Hsu and Stanford’s Ami Bhatt, Michael Bassik, and Lacramioara Bintu, had an idea for a gene editing company that would harness a category of enzymes called large serine recombinases (LSRs), which bacteriophage use in nature to insert their genomes into their bacterial hosts, to precisely insert therapeutic DNA payloads into safe harbor sites in the human genome. The friend suggested Cosmas should take a meeting with Patrick, and when the two jumped on a Zoom call, they hit it off right away.

Emily joined Raven just a few weeks later and started working with Cosmas and the rest of the team to diligence the Stylus opportunity. She was very familiar with gene therapy from her time as Chief Business Officer of Prevail Therapeutics (now a subsidiary of Lilly) and was immediately intrigued by the applications that could be opened up by durably and specifically inserting large therapeutic payloads into safe harbor sites. 

The LSR technology checked all of the boxes for us. LSRs have the potential to deliver significantly larger genetic payloads than what is possible with AAV. In addition, Cosmas and the Raven team saw the potential for the LSR system to be delivered non-virally via lipid nanoparticles, avoiding the immunogenicity issues seen with viral systems and enabling redosability. Finally, LSRs could insert genes into safe harbor sites in the genome, with efficiency that does not drop off for longer payloads, making this an ideal platform for safe, precise gene insertion. 

As the Raven team got to know the Stylus founders and the technical specs of the LSRs they had characterized, they and our TechAtlas colleagues spent months mapping and working up different potential therapeutic spaces where Stylus’ technology could be applied. Among other areas, we considered loss-of-function monogenic diseases, ex vivo cell therapy, and in vivo cellular reprogramming, all the while considering the delivery technology that would be necessary to deliver the LSR and its payload to create a therapeutic for a given disease – i.e., whether delivery would be needed to the liver, T cells, muscle, eye, heart, lung or beyond – as well as the competitive landscape in each disease space. 

The team landed on in vivo CAR‑T as a compelling use-case for which Stylus’s platform is uniquely well-suited. Traditional CAR‑T therapy has been transformative for oncology and involves engineering a cancer patient’s T cells to attack their tumor cells. It requires harvesting the patient’s blood cells, transforming them into CAR‑T cells in a cellular engineering process that takes place outside of the body and can take weeks, then infusing them back into the patient. It also requires giving chemotherapy to clear out the immune system and make room for the CAR‑T cells. 

In contrast, in vivo CAR‑T would involve delivering the genetic instructions directly to a patient’s T cells to reprogram them to attack and kill tumor cells. Stylus’s therapy would be ​“off-the shelf,” which could expand access to CAR‑T beyond specialized academic centers and benefit a broader patient population. Furthermore, directly editing a patient’s resident T cells would avoid the risks and side effects of the pre-treatment chemotherapy, and a patient wouldn’t need to wait precious weeks for the CAR‑T cells to be engineered. LSRs have the potential to enable safe, precise in vivo CAR‑T therapy and transform patient care in oncology and beyond. 

A hands-on build

As our excitement grew about the therapeutics Stylus’ technology could enable and the potentially curative impact those therapies could have for patients, our Raven team got to work on the build plan for the company: what our experimental plan would be, what target product profiles we’d seek to hit, who we’d need to hire, what lab space and equipment would be necessary, and what raise size was appropriate, and what corporate goals we’d seek to achieve with that financing. 

The Series A financing closed in the second half of 2022 and we were off to the races.

At Raven we have no single approach to building companies with scientific founders, but suffice it to say this was on the hands-on and collaborative end of the spectrum. At the time of the first financing, Emily stepped in as Stylus’ Interim CEO, Cosmas took on the role of Interim CSO, and Raven president/​RA Capital partner Josh Resnick joined the board. Other Raven colleagues including Emily Gransky, Kat Riesen, and Jerry Sewack took the lead in setting up Stylus’ finance, HR, and IT systems and recruiting the permanent team; and Peyman Hosseinchi, Raven Senior Associate, rolled up his sleeves helping to kickstart early experiments. 

We decided to team up with Khosla Ventures to fund and build the company together. Nessan Bermingham, Operating Partner at Khosla, is a serial biotech entrepreneur who founded the CRISPR pioneer Intellia Therapeutics as well as multiple other companies in the genetic medicines space. We knew Ness’ expertise and experience would make him an ideal partner and were excited to work with him as the Interim Chair of Stylus, and he and Josh remain on the board today. 

This group and the academic founders (Patrick, Ami, Michael, and Lacra plus Matthew Durrant and Josh Tycko) worked closely together to hire an impressive yet lean team in a matter of months. The team worked to build out an office and lab in Kendall Square, advance the science, prioritize the platform’s ​“killer apps,” and determine strategic pathways through the clinic and to market. Over time we passed the baton to the amazing team we recruited to run Stylus, led by chairman and CEO Emile Nuwaysir, and including seasoned industry scientists in the genetic medicine and CAR‑T fields, and they’ve already surpassed our super high expectations. 

What’s past is prologue

Our commitment to building and then operating Stylus reflects our conviction in the potential of precision genetic medicines and our approach to company building. At RA Capital, we are focused on developing therapeutically relevant solutions to the problems that are most challenging for patients and their families; this relentless focus allows us to move quickly to apply the right technology to the right patient unmet need when we find it. 

We also know we cannot crack the toughest medical problems alone. During the Stylus build, we benefited enormously from the collaboration and insights of our scientific founders along with Ness and our colleagues at Khosla Ventures. We know that the right team is just as important as the right technology, and were proud to be able to deploy Emily, Cosmas, and other Raven leaders to build such an awesome team of innovators and operators who could accelerate the buildout of Stylus’ platform and the advancement of therapeutic programs towards the clinic. And we fund our companies to ask the difficult scientific questions early, while the company is still lean, and then are excited to continue participating in financings over time, enabling sustained value creation. 

So consider us extremely proud parents. Stylus has the team and the technology to write the future of genetic medicines, as their presentations this week at ASGCT will show. They’re starting with a focus on potentially life-changing therapies for cancer patients, and we can’t wait to see where they end up.