With $45M, Mammoth Bio Expects Big Things From Tiny CRISPR Cas14

Xconomy San Francisco — 

Mammoth Biosciences set out to develop CRISPR-based diagnostics that could be faster and cheaper than what’s available today. Those diagnostics are still on the way, but Mammoth now has a new piece in its toolbox that could broaden the reach of these tests and expand the startup into therapeutic applications.

To support development of these new products, South San Francisco-based Mammoth has raised $45 million in financing. The Series B round of funding was led by Decheng Capital.

CRISPR technology uses enzymes to cut DNA or RNA in certain places, allowing the genetic sequence to be edited. Cas9 is the most widely known of these enzymes. Mammoth has been working with versions of Cas12 and Cas13, among others. With the new financing, CEO Trevor Martin says his company will focus particularly on Cas14.

Discovered by Mammoth’s co-founders based on their research at the University of California, Berkeley, Cas14 is about one third smaller than Cas9. That smaller size enables it to target anywhere on the genome and get to places that Cas9 can’t, making it appropriate for “when you want to have CRISPR as a scalpel rather than a sledgehammer,” Martin says.

This approach should avoid the off-target effects that are a concern with therapies that use Cas9, Martin says. Also, Cas14 comes from single-celled organisms called archea, which should avoid the immune responses that can be prompted by Cas9, which is derived from bacteria, he adds. Furthermore, the Cas14 enzyme fits with where many CRISPR therapies are trying to go next—in vivo gene editing, or edits inside the body. Whereas Cas9’s size makes it heavy cargo for the viruses or nanoparticles used to deliver therapies, Martin says Cas14 could be just right.

Though Mammoth plans to work on new CRISPR therapies, Martin says that the Cas14 research will have a more immediate impact on the company’s diagnostics research. A CRISPR diagnostic uses enzymes to seek out a pathogen and snip DNA or RNA from it in order to generate a readable signal. One common analogy for CRISPR is that it acts like molecular scissors, snipping away at genetic material.

“That’s not wrong, it’s incomplete,” Martin says. “The way we think about it is it’s a search engine for biology.”

Mammoth says its CRISPR technology can search for and find nucleic acids that are indicative of illness in a patient sample. With that capability, the company is developing tests for conditions ranging from infectious disease to cancer.

Developing Cas14-based products could steer Mammoth clear of patent problems similar to the disputes about the origins and ownership of CRISPR Cas9. Three years ago, the US Patent and Trademark Office ruled in favor of the Broad Institute of MIT and Harvard. But those patents continue to be in dispute. Meanwhile, Broad spinout Sherlock Biosciences is developing CRISPR-based diagnostics that use Cas13.

Martin says it’s too soon to say when a Mammoth medicine or diagnostic using Cas14 might reach clinical testing. But in the nearer term, he says the company is looking to work with large pharmaceutical and diagnostics companies, helping them develop their products. He won’t say which diseases Mammoth will target, though he revealed that the company already has partnership with the University of California, San Francisco, to develop a coronavirus diagnostic.

“Today, we still we don’t have a rapid way of doing molecular diagnostics at scale—it just doesn’t exist,” Martin says. “This technology has the capability of doing that.”

That alliance came about through UCSF scientist Charles Chu, who is also a member of Mammoth’s scientific advisory board. Martin declined to describe funding details of the partnership or offer a timeline for the development of a coronavirus test, other than to say “as soon as possible.”

To date, Mammoth says it has raised more than $70 million. Other investors in Mammoth’s latest financing include Mayfield; NFX; Verily, the biotech R&D spinout from Google parent Alphabet; and Kleiner Perkins co-founder Brook Byers.

Image of woolly mammoth by Flickr user Firehawk Hulin via a Creative Commons license. Image has been cropped to fit Xconomy publishing system standards.