Crispr Therapeutics AG, a start-up formed by the co-inventor of the CRISPR/Cas9 genome-editing technology, closed a $25 million series A round that will fund the translation of this hugely popular approach from the academic lab to the clinic.
Emmanuelle Charpentier, who holds positions at Hanover Medical School in Germany and at Umeå University in Sweden, published seminal papers in Nature in 2011 and in Science in 2012 that have spawned rapid, widespread adoption of the CRISPR/Cas9 system for genetic manipulation of countless model organisms.
Joining her as scientific founders is a multidisciplinary line-up of American scientists, including: 2006 Nobel laureate and RNAi pioneer Craig Mello, of the University of Massachusetts Medical School, in Worcester, Mass.; RNA delivery expert Daniel Anderson, of Massachusetts Institute of Technology; stem cell scientist Chad Cowan of Harvard University; and gene therapy and genome-editing expert Matthew Porteus, of Stanford Medical School.
Despite its strong American flavor, the company is headquartered in Basel, Switzerland, although its main operational base will be in London. "We decided to go to Europe, one of the reasons being that Europe has a really strong network in gene therapy," CEO Rodger Novak told BioWorld Today. Novak was previously a co-founder of Vienna-based Nabriva Therapeutics GmbH, an anti-infectives spinout from Sandoz GmbH, and he later headed up Paris-based Sanofi Group's global anti-infectives R&D group.
The funding, which has come solely from Basel-based Versant Ventures, is earmarked for preclinical and possibly early clinical development of therapies in as-yet-undisclosed indications. "The $25 million will be exclusively used to fund two to three programs in the area of CRISPR/Cas, to bring them to the IND or CTA [clinical trial application] stage," Novak said. The cash could extend to a first-in-man study, which would, by default, be a phase II trial. "You can't do it in healthy volunteers," he said.
Given the novelty of the technology, Crispr Therapeutics aims to reduce some of the technical and clinical risk by focusing initially on indications that do not require systemic delivery. Cell therapies, including stem cell therapies, that involve ex vivo genome editing and therapies for ophthalmology indications are candidates for further study, but the company has not yet pinned down the conditions it will focus on first.
"We are being very careful about which are the indications to go after first, to give us a high likelihood of success. We don't want to promise the world," Tom Woiwode, partner at Versant Ventures, told BioWorld Today. The slow progress at translating siRNA-based therapeutics into products offers a cautionary precedent. There is, however, a key difference between the two technologies. "SiRNA is an inherently transient modification," he said. In contrast, CRISPR/Cas9 alters its target DNA locus permanently.
Academic scientists have been attracted by the CRISPR/Cas9 system's ease of use and low cost in comparison with other genome-editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases (TALENs), both of which rely on complex DNA-protein interactions. "Very soon it will be a little bit like PCR," Charpentier told BioWorld Today. "It's a very democratic tool."
The technology is derived from a form of microbial immunity that relies on hypervariable genetic loci, called clustered regularly interspaced short palindromic repeats (CRISPR). Those store DNA snippets from invading plasmids and bacteriophage, which are transcribed and processed into RNA molecules, called CRISPR (cr) RNAs. Those guide a Cas9 nuclease to the complementary site on invasive plasmids or phage, where they catalyze double-stranded DNA breaks and enable further modifications to be introduced.
Charpentier, her research collaborator Jennifer Doudna, of the University of California, Berkeley, and co-workers, described in the Aug. 17, 2012, issue of Science the key step in the development of the technology, the production of a chimeric RNA molecule, comprising a mature crRNA and its trans-activating crRNA (tacrRNA) counterpart, with which it ordinarily forms a two-RNA structure. Reprogramming that guide RNA (gRNA) molecule enables users to direct the Cas9 activity to any genetic locus of interest.
Doudna is among the founders of a rival firm, Cambridge-based Editas Medicine, which raised $43 million last year. "There's room for a couple of players," Novak said. "I do expect one or two other players to come into the game." (See BioWorld Today, Nov. 25, 2013.)
Earlier this month, the Broad Institute of Harvard and MIT claimed to have received the first U.S. patent grant on CRISPR/Cas9 technology, arising out of the work of another Editas co-founder, Feng Zhang. Crispr Therapeutics' patent applications are still being processed. Because of Sweden's IP rules, Charpentier has personal ownership of her inventions. "We not only believe it – it's a fact that we remain uniquely positioned as the only company with access to the foundational IP for use in human therapeutics," she said.
Moving the CRISPR/Cas9 system from academic labs into human patients requires further refinements of the technology to minimize the risk of off-target effects, to improve the efficiency of CRISPR/Cas9 uptake, and to iron out issues relating to chemistry, manufacturing and control (CMC).
"For some of the applications, we're not years away from reducing it to practice," Novak said. An outstanding task remains the development of additional functional genetox assays, to assess the safety of specific therapies. "You need to make sure your off-target activity is so low your risk-benefit ratio is on the side of the benefit." Human trials may not be far off. "Assuming we have a pretty straightforward ride, with some effort and a little bit of luck, you could see the first clinical trial in maybe three years' time," he said.