antigen receptor T-cell therapy, or CAR-T, which in early clinical studies has had notable results stopping people’s blood-borne cancer in its tracks. (And one of its purveyors, Juno Therapeutics, just filed to go public less than a year after its emergence from stealth.)
CAR-T is already a gene-modification technology: T cells are removed, genetically engineered to seek out tumor cells with a specific protein on their surface, and put back into the patient. But CAR-T also generates a powerful immune response that can overwhelm a patient with inflammation, an effect that a more precise gene-editing approach–which CRISPR/Cas9 might be—might ameliorate.
Bermingham cautioned that, as with any new technology with grand expectations, it’s important for a small company to choose wisely. “You want to ensure you’re using the system for right therapeutic application,” he says. “There are examples historically of a drug developed using a new platform, but then small molecules”—in other words, the older, cheaper, better understood standby—“came along to make the new product nonviable.”
There are several decisions to make. As with RNAi, delivery into various cell types could be a problem and require a raft of experiments and questions. For example: Should the CRISPR/Cas9 complex—a large enzyme (that’s the Cas9) attached to a nucleic acid strand—be full-sized before it goes into the cell, or should it be encoded, jammed into a viral vector (a well known delivery method in gene therapy), and only expressed once it’s in the cell?
Fortunately for Intellia and its rivals, years of efforts to deliver gene therapy, RNA-mediated drugs, and the like have built a library of data “that we can co-opt,” says Bermingham. “We can’t say what will work right now, but we know how to test it. We’re not starting from zero.”
There’s also a peculiarity of CRISPR/Cas9: so far, the system everyone uses is borrowed from the bacterium S. pyogenes. And it works fine as long as the gene you want to edit is near a specific sequence of the A-C-T-G amino acids that comprise DNA. (The S. pyogenes Cas9 happens to like “GG,” which is good, because there’s a lot of GG sprinkled around the genome.) But inevitably there will be genes to modify or delete nowhere near a “GG,” which means researchers will need a Cas9 from a different bacterium.
Caribou is building a library of Cas9 variations, testing delivery technologies, and a lot more. It has an equity stake in Intellia, and Intellia will have access to its entire platform. “We co-founded Intellia together,” Haurwitz says. “It’s a joint mission and based on a heavy assumption that Intellia can be successful because of [its] privileged relationship with Caribou.”
Haurwitz and Caribou chief scientific officer Andy May are on the Intellia board of directors, joining Bermingham, Atlas partner Jean-Francois Formela, and Leonard.
The scientific founders are Rodolphe Barrangou of North Carolina State University, Erik Sontheimer of the University of Massachusetts Medical School, and Luciano Marraffini of Rockefeller University.
The Novartis investment comes from its research group, the Novartis Institutes for Biomedical Research (NIBR), not from its venture group. NIBR is headquartered in Cambridge. There is no technology agreement between Novartis and Intellia, Bermingham says.
