Scribe Therapeutics, a University of California, Berkeley, spin-off dedicated to designing new-and-improved CRISPR gene-editing systems, has raised $100 million in series B financing. CEO and cofounder Benjamin Oakes says the money will help Scribe expand its 30-person team, build up its enzyme engineering platform, and accelerate development of gene-editing therapies for neurodegenerative diseases.
Many companies developing CRISPR gene-editing therapies use variations of CRISPR-Cas9, the original gene-editing system described by UC Berkeley’s Jennifer Doudna in 2012. Since then, Doudna’s group and others have looked for alternative Cas enzymes with better or different properties for gene editing than Cas9. One result of Doudna’s search is an enzyme dubbed CasX.
In 2018, Doudna, Oakes, UC Berkeley biochemist David Savage, and former Doudna postdoc Brett Staahl co-founded Scribe to make gene-editing therapies based on CasX. The company was in stealth until it announced raising $20 million in series A financing on Oct. 6, 2020. A day later, coincidentally, Doudna and her colleague Emmanuelle Charpentier won the Nobel Prize in Chemistry for their creation of CRISPR-Cas9 gene editing.
CasX has some features that could give it an upper hand over Cas9 as a gene-editing therapy, Oakes explains. For one, CasX is a smaller protein than Cas9, which should make it easier to get into cells in the human body with gene-therapy delivery vessels like adeno-associated viruses, he says. But neither CasX nor Cas9—both of which are part of bacterial immune systems—evolved for editing genes in humans. And Oakes sees room for improvement.
As a PhD student in Doudna’s and Savage’s labs, Oakes worked on engineering new versions of Cas9. In one study, Oakes created a version of Cas9 whose DNA cutting is allosterically controlled by small-molecule binding. In another study, he used a protein-engineering trick called circular permutation to create a version of Cas9 whose DNA-cutting ability is kept off until protease enzymes cleave a chemical lock that allows Cas9 to begin cutting.
Scientists at Scribe are applying techniques like these to make CasX more like a drug, Oakes says. The start-up is also creating millions of new versions of CasX in search of ones with editing properties superior to Cas9. “We have enzymes that are equivalent to if not significantly more active and more specific than Cas9,” Oakes says.
Although Scribe continues to improve CasX, it has started working on gene-editing therapies for neurodegenerative disease with versions of the enzyme that it already created. In October, the start-up announced a partnership with Biogen to create CasX-based therapies for genetic forms of amyotrophic lateral sclerosis (ALS) and an option to work on another undisclosed neurological disease target. Scribe got $15 million from Biogen, and could earn more than $400 million in milestone payments between the two programs.
In addition to the potential therapeutic benefits, Oakes mentions a more pragmatic reason for creating new CRISPR systems: the patent issue. By creating CRISPR systems based on CasX, Scribe should be able to circumvent the bitter CRISPR patent disputes that largely center on the use of Cas9.