![Firm focuses on diseases caused by protein folding and has a Phase III candidate. [© Daniel Tackley - Fotolia.com]](https://www.genengnews.com/wp-content/uploads/2018/08/Sept1_2010_2578677_PurpleProtein_PfizerBuysFoldRx9564149762-218x150.jpg "DNA Changes that Don’t Change Protein, Still Affect Function in Time")
Scribe Therapeutics has completed an oversubscribed $100-million Series B financing, with aims to further develop its suite of custom gene-editing and delivery technologies based on molecular engineering, as well as advance a pipeline of gene-edited therapeutics for neurodegeneration and other diseases with high unmet need.
Scribe’s co-founders include 2020 Nobel laureate Jennifer Doudna, PhD, a biochemist at UC Berkeley; David Savage, PhD, scientific advisor and fellow Berkeley professor; and the company’s president and CEO Benjamin L. Oakes, PhD. As an entrepreneurial fellow at the Innovative Genomics Institute, Oakes worked in the labs of Doudna and Savage, developing CRISPR-Cas9 molecules with enhanced characteristics.
“It’s part of this community where we can all come together and discuss not only the new ideas that Scribe has, but the new ideas that are going on around the world. It’s something that we try to do quite often,” Oakes told GEN Edge, because it’s not only strategically useful but also enjoyable. “That’s what we want to do with people we like.”
Doudna’s status as co-winner of the 2020 Nobel Prize in Chemistry—shared with Emmanuelle Charpentier, PhD, of the Max Planck Institute for developing the CRISPR “genetic scissors” for gene editing—was not a big factor for investors. “I don’t think I talked about it even once, or had anyone ask about it even once,” Oakes recalled. Of greater interest was Scribe’s ability to develop and deliver CRISPR-based gene-edited medicines at the nexus of several technologies.
“We have DNA synthesis currently going through the roof. We have DNA sequencing massively expanding. We have the ideas of synthetic biology coming in. And then you have CRISPR, with the ability to profoundly manipulate any location in the human genome,” Oakes said. “Biology today is able to ask questions and answer them much more quickly than it has ever been able to do even five years ago.”
Oakes predicts an “utter transformation” for the future of medicine, “how we even think about disease, how we understand disease and then, of course, how we can treat it. That is my hope.”
New wave company
“Scribe’s engineering-first philosophy has resulted in a uniquely flexible platform for imagining and creating a new era of CRISPR-based therapies to elevate the standard of care for thousands of patients,” Doudna stated.
That platform, according to Scribe is designed to address four challenges faced by CRISPR drug developers: Safety, delivery, poor editing outcomes, and the uncertainty rekindled in 2019 by the bitter legal battle over who invented CRISPR-Cas9.
To avoid the intellectual property uncertainty, Scribe has engineered its own CRISPR effectors—CasX enzymes—that are more capable of delivering CRISPR via a viral vector because the protein is less than 1,000 amino acids (aa), compared with the 1,200–1,400-aa size of Cas9.
Those “X-Editing” (XE) molecules, the first to be engineered by Scribe, are highly engineered CRISPR-based enzymes designed to provide combined aspects of greater efficacy, specificity, and deliverability than currently available CRISPR genome editing technologies.
“By building our platform on CasX, we can actually now start to really utilize AAV much more efficiently, coupled with the fact that we’re engineering these enzymes to fundamentally cut DNA more effectively, and do so very specifically,” Oakes said.
CasX enzymes were first detailed as a third platform for RNA-programmed genome editing: “The compact size, dominant RNA content, and minimal trans-cleavage activity of CasX differentiate this enzyme family from Cas9 and Cas12a,” a research team led by Doudna explained in a 2019 study published in Nature.
Oakes added: “The CasX molecule that came directly out of the ground does not cut DNA well, so we’ve actually taken over 100 steps in sequence space—100 different changes stacked on top of each other, away from that natural enzyme. That’s a process that is continuing.”
Engineering first, Oakes said, has the advantage of preventing Scribe from getting too wedded to a specific approach to developing technology or treatments, even XE.
“It ensures that we don’t stagnate. It’s hard to not get stuck on a specific technology. But we are always making these iterative changes to improve our enzymes and our enzyme systems,” Oakes said. “There will absolutely be improved versions of the X-Editor that will be more specific and more active, and perhaps have other interesting characteristics.”
Scribe’s engineering platform creates custom molecules specifically designed for therapeutic use within the human body with an eye toward improved efficacy, specificity, and deliverability. The company says it generates “hundreds” of synthetic CRISPR molecules each month, incorporating the most promising ones into a fully integrated set of genome-editing modalities.
To date, Scribe says, it has engineered natural CRISPR enzymes into millions of novel variants with therapeutic attributes intended to enable highly effective and specific in vivo treatments.
“We set out to build Scribe by essentially identifying a couple of entirely new foundations for genome editing, and then picking ones that have really significant advantages” Oakes said.
“We built Scribe to essentially apply design and engineering-based philosophies to solve the challenge that we saw in front of us, which was both technical—building more efficient, more specific, more deliverable molecules—as well as pragmatic—actually understanding who owns these molecules, and how we can apply them to bring value, not only back to the company and its shareholders, but also really back to patients.”
Scribe’s pipeline includes treatments being developed through collaboration potentially worth $400 million with Biogen launched last year, focused on treating neurodegenerative disorders with CRISPR-based therapies. The companies are developing therapies to address genetic causes of amyotrophic lateral sclerosis (ALS), which aligns with Biogen’s core growth area of neuromuscular disorders. “In our ability to utilize AAV more effectively, we believe that we have a real differentiated advantage in the CNS, as well as other areas,” Oakes said.
Scribe’s pipeline, he added, extends beyond neurodegenerative treatments to ophthalmological diseases; multi-system, muscle, and metabolic disorders; and hematopoietic disorders.
Avoro Ventures and Avoro Capital Advisors led the Series B financing, joined by OrbiMed Advisors and Andreessen Horowitz, which led Scribe’s $20 million Series A financing, completed in October 2020.
Perceptive Advisors, funds and accounts advised by T. Rowe Price Associates, Inc., funds managed by Wellington Management, RA Capital Management, Menlo Ventures, and an undisclosed global investment firm also joined the syndicate.
As part of the financing, Behzad Aghazadeh, managing partner at Avoro Ventures and Avoro Capital Advisors, and Carl L. Gordon, managing partner at OrbiMed Advisors, will join Scribe’s Board of Directors.
How soon before Scribe pursues a Series C financing? Or goes public?
“The next round is not something we’re contemplating just yet. I’m excited to see all of the amazing things we’re going to accomplish with the resources we’ve gathered so far,” Oakes said.
Oakes expects Scribe to double its headcount, now at 30 employees. He’ll have the challenge of managing that growth without sacrificing its community-driven culture.
“Our culture and our community are so important. We are trying to grow within our means,” Oakes said. “This is a company that I’ve poured every ounce of energy I have into, and that’s because it’s not a company—it’s a community, and that’s the way that I want to keep it.”
