Regeneron will use Mammoth Biosciences’ tiny Cas enzymes to deliver in vivo CRISPR-based gene editing therapies to tissues and cell types beyond the liver, the companies announced Thursday.
Regeneron is paying $100 million to work with Mammoth Biosciences on delivering in vivo CRISPR-based gene editing therapies to multiple tissues and cell types, the companies said Thursday.
New York-based Regeneron is paying $5 million upfront and investing $95 million in Mammoth to form the alliance. Mammoth is eligible to receive up to $370 million in milestones per target and has the right to opt-in to co-funding and sharing profits on “a majority of collaboration programs” in lieu of milestones and royalties.
The companies have potentially complementary technologies that could combine to address one of the key barriers to wider use of genetic medicines. Scientists know the genetic causes of many diseases and in CRISPR they have a system for editing DNA to cure patients. However, the vectors typically used to deliver genetic medicines are too small to carry normal CRISPR-Cas systems and can only target the liver.
Mammoth has a potential solution for the capacity problem. Adeno-associated viruses (AAV) vectors can carry genes up to 4.7 kb. Cas9, a widely used CRISPR enzyme, is 4.1 kb. The size makes it impossible to simply pack Cas9 and associated gene-editing machinery into a single AAV vector.
Researchers have come up with a range of potential workarounds. Mammoth’s answer is to use smaller Cas enzymes. Commonly used variants of Cas9 and Cas12 have 1,300 or more amino acids. Mammoth’s NanoCas and CasPhi have around 450 and 750 amino acids, respectively. The size makes it possible to put the enzymes, guide RNA, tissue-specific promoters and other molecules in an AAV vector.
For its part, Regeneron is developing AAV vectors that could answer the question of how to target tissues beyond the liver. The drugmaker is drawing on its expertise in antibody engineering to add targeting elements to AAV vectors. By attaching antibodies to viral vectors, Regeneron could create vehicles capable of delivering genetic payloads to specific tissues and cell types around the body.
Regeneron has high hopes for the vectors. Ryan Crowe, senior vice president of investor relations and strategic analysis at Regeneron, answered “genetic medicine” last month at a TD Cowen conference when asked what aspect of the company is most underappreciated by investors. Crowe’s answer reflected Regeneron’s work on delivering this class of medicines.
“We think that delivery is right now a huge bottleneck in genetic medicine, and we are working on an approach to use our antibodies to better target genetic payloads to target tissues so that the payloads aren’t chewed up by the liver. This would reduce the manufacturing requirements and also be probably a lot safer than gene therapies today,” Crowe said.
The push into genetic medicines still has “years to play out,” Crowe noted. Regeneron has secured “broad access” to Mammoth’s editing technologies for five and a half years, plus the option to extend the arrangement by two years. Certain targets are excluded from the deal. The collaborators will jointly select and research targets. Regeneron will lead development and commercialization activities.
Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.
