Trevor Martin, PhD, CEO and co-founder of Mammoth Biosciences

Mammoth Biosciences said today that it has exclusively licensed patents granted by the U.S. Patent and Trademark Office to the regents of the University of California that cover CRISPR collateral cleavage diagnostic systems—a key milestone in the company’s effort to be the first to market a CRISPR-based disease detection platform.

U.S. Patent No. 10,253,365 and U.S. Patent No. 10,337,051 cover comprehensive techniques that will enable Mammoth to offer DNA and RNA detection diagnostics that apply CRISPR gene editing. Patent ‘365 covers Type V CRISPR-Cas effector proteins for cleaving single stranded DNAs (ssDNAs) and detecting target DNAs, while patent ‘051 covers methods and compositions for detecting a single-stranded target RNA.

“Essentially, collateral cleavage serves as an amplification and a readout for saying the CRISPR protein successfully identified whatever nucleic acid you told it to identify,” Mammoth Biosciences CEO and co-founder Trevor Martin, PhD, told GEN. “This technique gives you exquisite sensitivity and specificity like the best molecular techniques, but you’re getting it in a multiplexable, isothermal, very easy-to-use format.”

“The specificity is an especially great aspect of the CRISPR system,” Martin added. “You can even do really specific SNP analysis using this system, while still maintaining a great level of sensitivity, and, on top of that, carry out multiplexing.”

Martin is among five co-founders of Mammoth, a group that includes CRISPR pioneer Jennifer Doudna, PhD, of UC Berkeley—who is listed as an inventor on both patents.

Martin and Doudna co-founded Mammoth along with Lucas Harrington, Mammoth’s chief discovery officer; Janice Chen, PhD, the company’s chief research officer; and Ashley Tehranchi, PhD, who served as CTO until May.

Doudna, Harrington, and Chen are listed at co-inventors of Patent ‘365, along with Enbo Ma, senior staff scientist in Doudna’s lab.

On Patent ‘051, Doudna is listed among co-inventors, which include three former graduate students in her lab—Mitchell R. O’Connell, PhD, now a principal investigator at University of Rochester (NY) Medical Center; Alexandra East-Seletsky, PhD, now a scientist with Arrakis Therapeutics; Spencer Charles Knight, PhD; and Doudna’s husband Jamie H.D. Cate, PhD, professor of chemistry, bbiochemistry, and molecular biology at UC Berkeley.

Mammoth’s co-founders brought the company from stealth mode in April 2018, disclosing plans to develop an easy-to-use and affordable point-of-care test enabling fast, simultaneous detection of multiple conditions, in real-time, both in the hospital and at home, through a single credit card-sized strip form factor.

Results, Advice in 15 Minutes

Once at-home users complete the test, Mammoth envisions them securely uploading an anonymous photo of the strip to the company’s corresponding application for remote analysis. According to the company, users can receive their confidential results and professional advice, all in potentially less than 15 minutes, without having to collect samples and mail them for analysis.

A year ago, Mammoth raised $23 million dollars to fund the initial development of the test. The diagnostics apply CRISPR to search and find DNA or RNA that indicate the presence of disease, akin to how Google searches for information on the Web.

Mammoth’s platform publicly uses three unique CRISPR proteins: Cas12, which targets double-stranded DNA; Cas13, which targets and recognizes single-stranded RNA; and Cas14, which targets ssDNA. Used together, the proteins enable the diagnostic to sense virtually any type of nucleic acid.

All three are programmable by a guide RNA (gRNA) protein that matches up with the sequence users want to detect. Then, the protein cleaves reporter molecules to confirm a match has been found.

“You first bioinformatically design a gRNA for those targets. The gRNAs are going to be specific to the proteins and target, and that’s how you program the CRISPR proteins to identify malaria versus Ebola or something else,” Martin said.

Once Cas12, Cas13, or Cas14 finds its matching target, the protein can cleave the reporter molecules, for example, producing a color change that indicates the presence of a specific DNA or RNA sequence.

Mammoth has committed itself to “democratize disease detection” by developing easy-to-use, affordable, and effective tests usable in a variety of formats from central labs and point-of-care settings, such as hospitals and clinics, to even home use.

“In a lab setting, you can have a different level of targets you’re going after. In a consumer setting, you’d want it in a very simple, easy-to-use form factor and, most importantly, that’s easy to understand,” Martin said. “At Mammoth, we’re most focused on delivering information that’s actually actionable.”

“A Great Validation”

Mammoth is one of at least two companies founded by CRISPR pioneers focused on developing diagnostics using the gene editing technology. In March, Feng Zhang, PhD, of The Broad Institute of MIT and Harvard was among co-founders who launched Sherlock Biosciences. Sherlock has said it plans to leverage synthetic biology and intellectual property related to the CRISPR patents held by the Broad and Harvard University’s Wyss Institute.

Sherlock takes its name from one of its two core technologies—Specific High-sensitivity Enzymatic Reporter unLOCKing (SHERLOCK). The other core technology is dubbed INSPECTR (INternal Splint-Pairing Expression Cassette Translation Reaction), a molecular diagnostic platform using synthetic-biology developed in the Wyss Institute lab of company co-founder James J. Collins, PhD.

“At Mammoth, we think competition is great, and it‘s just further validation of how exciting this technology is,” Martin said. “Our patents are really a great validation of Mammoth being at the forefront of this field.”

Martin said Mammoth is looking at applications for its diagnostic technology that go beyond healthcare. The company, he said, is developing tests and teaming up with diagnostic partners to explore applications in industries that include agriculture, oil and gas, and forensics.

Mammoth is not disclosing its partners or its pricing for its diagnostics, though Martin did say the company is looking to increase its accessibility to consumers.

“We’re really trying to make it so that you don’t always have to go necessarily to the doctor’s office to get molecular information about your health,” Martin added. “We can be a catalyst for the rest of the healthcare system to actually be delivered to the point of care.”

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