Excision BioTherapeutics has become the first company to exclusively license new CRISPR systems discovered last year by Jennifer Doudna, Ph.D., a pioneer of the gene-editing technology, and Jillian Banfield, Ph.D., for use in developing treatments against infectious diseases.


Excision has licensed the new CRISPR (clustered regularly interspaced short palindromic repeats) systems for use from the University of California, Berkeley, under an agreement announced today, and whose value was not disclosed.


The new gene editors, discovered from uncultivated microbes, enable the development of new versions of CRISR genome-editing technology, using additional nucleases besides the familiar Cas9.


“A lot of them are smaller, first off, and they can be more packageable. They can potentially be able to be delivered using smaller viruses like adeno-associated virus (AAV). So that’s one advantage,” Thomas Malcolm, Ph.D., Excision’s founder, president and CEO, told GEN. “On the business front, they offer just a cleaner business landscape. There’s very clear intellectual property out of UC Berkeley compared to Cas9.”


UC Berkeley, the University of Vienna, and Emmanuelle Charpentier, Ph.D., a director at the Max-Planck Institute in Berlin, are in a legal battle with the Broad Institute of MIT and Harvard over who invented CRISPR/Cas9. On October 25, the Broad filed a brief with the U.S. Court of Appeals for the Federal Circuit seeking to uphold the February 15 decision by the Patent Trial and Appeal Board (PTAB). The PTAB found “no interference in fact” between 12 CRISPR-related patents that list as inventor Feng Zhang, Ph.D., of the Broad, and a patent application by Drs. Charpentier and Doudna.


Dr. Malcolm said Excision is looking to use the nucleases it is licensing from UC Berkeley in addition to Cas9, in order to expand its pipeline of treatments. The company has added to its pipeline EBT105, a herpes simplex virus type 2 (HSV-2) candidate that applies gene editing through a triplex guide RNA (gRNA) excision knockout, and EBT106, a hepatitis B virus candidate that uses a duplex gRNA excision knockout.


Excision’s pipeline is anchored by EBT101, a human immunodeficiency virus-1 (HIV-1) candidate applying a multiplex gRNA excision knockout gene edit using Cas9. EBT101 and is on track to advance into clinical trials in the fourth quarter of 2018 or first quarter of 2019.


Also using Cas9 are EBT103, a JC virus candidate applying a duplex gRNA excision critical element, and EBT104, an HSV-1 candidate applying a triplex gRNA excision knockout.

“A De-risking Factor”

We’re not going to replace those. There’s no need to. We have a very strong intellectual property position with those Cas9 therapeutics,” Dr. Malcolm said. “But if—and this is a big if—there are for some reason unforeseen scientific challenges, we have alternatives as well. It’s really a de-risking factor.”


He said Excision is looking to use both CRISPR/Cas systems discovered in uncultured bacteria and identified as CasX and CasY by Drs. Doudna and Banfield in “New CRISPR–Cas Systems from Uncultivated Microbes,” a research paper published February 9 in Nature. CasX and CasY were validated in Escherichia coli in Dr. Doudna’s lab.


“We show that that metagenomic discoveries related to CRISPR-Cas systems are not restricted to in silico observations, but can be introduced into an experimental setting where their activity can be analyzed,” the Doudna–Banfield team concluded.


“Given that virtually all environments where life exists can now be probed by metagenomic methods, we anticipate that the combined computational-experimental approach will greatly expand the diversity of known CRISPR-Cas systems, enabling new technologies for biological research and clinical applications.”


Excision’s licenses from UC Berkeley give the company the right to sublicense the new CRISPR gene editors to biopharma companies and other entities, providing them with new research alternatives as they seek to develop new treatments.


“It really opens up for us an opportunity to begin to partner with other companies that may be interested in working on other infectious diseases outside the scope of our pipeline with these new editors,” Dr. Malcolm added. “We’re excited about partnering and really trying to conquer as many viruses as we can in partnership.”

Looking toward Partnerships

As for types of partnerships, he added, “I’m really leaning toward sponsored research-type programs, because we have the ability to expand into a lot of lab space. We have a lot of lab space and a lot of scientific capability already.”


Excision is in talks with “multiple groups” to partner some of its pipeline programs, Dr. Malcolm said, declining to identify the groups or the programs under discussion. The company’s license with UC Berkeley covers human infectious viral diseases, and Excision isn’t looking “at this point” to partner outside of that therapeutic area, he said.


He isn’t sure, he said, whether CasX and CasY can be combined in use—but is more certain that they can complement Excision’s proprietary ViraSuite platform, which targets viral proteins to eliminate infection.


In September, Excision won $10 million in seed financing led by ARTIS Ventures. A “small” portion of funding went toward the license agreement with UC Berkeley, though the bulk of the capital went toward advancing lead program EBT101 into the clinic, Dr. Malcolm said.


The seed financing accounts for most of the $11.1 million in capital raised by Excision since it was founded in 2015 as a spinout of Temple University's Lewis Katz School of Medicine. Dr. Malcolm is among founders of the company, along with Kamel Khalili, Ph.D., principal scientific advisor and professor and chair of neuroscience at the Katz School; David Rowe, VP, business development-CRISPR editors; and Rob Simmons, VP, business development-CRISPR inhibitors. Excision has about 30 full- and part-time employees.


Dr. Malcolm said Excision has no plans to duplicate its lead program and other Cas9-based programs with treatments based on the new CRISPR systems it is licensing.


“There’s really no need for us at this time to develop an equivalent with the new editor,” Dr. Malcolm added. “It just wouldn’t be very cost effective for us to rewind the clock two years to begin this whole program, over with the limited funds that we have. We’re moving forward.”

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