By Aaron Krol
December 2, 2014 | Although the CRISPR-Cas9 system was only discovered in the fall of 2012, it has already attracted three companies betting that this powerful gene editing tool can be turned to drug development. Editas Medicine and Intellia Therapeutics, both of Cambridge, Mass., and their Swiss counterpart CRISPR Therapeutics, are all exploring CRISPR-based biotech drugs for indications as varied as infectious disease, cancer, immune disorders, and rare genetic diseases.
The Cas9 protein, first found in bacteria cutting up the genomes of invasive viruses, is in many ways the perfect tool for genetic engineering. The protein can be directed to almost any locus in any genome, where it cuts through both strands of DNA, and can be modified to add new genetic material to fill the gap. And unlike other systems like TALEN and zinc finger nuclease, CRISPR does not use its own elaborate molecular code to find its DNA target; it only requires a matching strand of RNA, making it easy to use and extremely flexible. (CRISPR stands for “clustered regularly interspersed short palindromic repeats,” a description of the signature bacterial DNA sequences that first pointed scientists toward Cas9.)
“It’s not just exciting science,” says Katrine Bosley, a serial biotech executive who became the first permanent CEO of Editas Medicine this summer. “It really is the beginning of a new frontier in genomic medicine. You think about the kinds of therapies you can potentially create with genome editing, and it’s a lot of things we’ve aspired to do for years and years.”
However, there are obstacles to CRISPR’s use in humans: Cas9 makes occasional off-target cuts that could be dangerous, and like most complex biomolecules, it’s difficult to introduce into cells, especially inside living bodies. This week, Editas announced a series of intellectual property agreements that the company hopes will shore up its path to creating a safe and effective platform for CRISPR-based drugs. Three separate deals, with the Broad Institute and Harvard University, Massachusetts General Hospital, and Duke University, respectively, will grant Editas exclusive license to use key CRISPR technologies in pursuit of human therapies. Together, these deals cover one issued patent, and numerous provisional patent applications.
“This is a unique combination of licensing rights across these multiple institutions,” says Bosley. “Each one has important, foundational science in the field of genome editing, but the combination of the three gives us a critical mass to make new therapies.”
Many of the properties licensed to Editas come from the labs of the company’s scientific founders: Feng Zhang of the Broad Institute, David Liu and George Church at Harvard University, and Keith Joung from Massachusetts General. (Editas’ fifth founder, Jennifer Doudna, is co-discoverer of the CRISPR-Cas9 system.) The Duke University properties come from the lab of Charles Gersbach, who is not a member of Editas but is partnering with the company on specific R&D programs.
One of the licenses secured by Editas this week, from David Liu’s lab at Harvard, covers a new drug delivery system, an important piece of the puzzle for turning CRISPR from a research tool into a therapeutic agent. Getting a large biomolecule like Cas9 past cell membranes and into a cell’s genetic material is a serious challenge. Liu’s solution, described in a Nature paper
this October, uses a coat of cationic lipids to sneak the protein inside cells. Cas9, or another gene editing protein like a TAL effector, is attached to an RNA or DNA molecule with a strong negative charge, which lets the entire complex bind with the positively-charge lipid structure. A fusion of the lipid coat with the cell membrane then allows the packet of gene-editing material to pass safely through.
Importantly, Liu and colleagues have already shown that this system can work inside the bodies of living organisms, successfully engineering cells in the inner ears of mice to express a red fluorescent protein. This is significant because Editas’ competitors, CRISPR Therapeutics and Intellia, have both stated that they will concentrate first on ex vivo applications, modifying cells outside the body before reinjecting them, for instance as part of an immune attack on cancer.
With the cationic lipid delivery system, however, Editas may have a shot at testing out in vivo drugs earlier in its development process, something that Bosley says is “certainly within the scope of programs we’ve started to work on.” She adds that she expects this tool to be Editas’ first delivery vehicle, for both in vivo and ex vivo programs. The active pursuit of in vivo therapies would be a landmark for CRISPR gene editing, opening up otherwise intractable hereditary diseases as possible targets for treatment.
Open for Innovation
The IP licensed to Editas in this week’s agreements also includes the first and only issued patent related to CRISPR, covering Feng Zhang’s work modifying the system to work in mammalian cells; and Keith Joung’s work with guide RNA to help minimize off-target cuts to the genome.
While the details of each agreement are different, negotiators have tried to strike a balance between Editas’ desire to gain a competitive edge in drug development, and open science principles that seek to make CRISPR technology broadly available, which are important to the company’s scientific founders. “Something like CRISPR is a foundation tool,” Zhang told Bio-IT World
in an interview this January
. “I think making sure these foundation tools are open is important… What my lab has done is try to make the information, the technical know-how, as well as the physical reagents, as accessible to everybody as possible.”
Editas’ deal with Harvard and the Broad Institute includes a clause that opens the relevant IP to third parties who want to pursue gene targets Editas is not working on itself. Editas hopes to pursue a large and diverse selection of gene targets, both internally and through partnerships with academic labs and other companies. However, the space of diseases that could potentially be impacted by CRISPR is so large that a single company would be hard pressed to monopolize the field.
“It is important that the technology be pursued broadly,” says Bosley. “If there are targets we’re not pursuing, and someone has a good idea to do that, I think it’s great to have this provision where they can come to us, or come to one of the institutions, and work together to find a way they can pursue it.”
Editas has not yet shared the specific diseases or genes it plans to go after, except to say that its active programs include both relatively simple applications of CRISPR, like attacking viral RNA and DNA, and more complex ones, like modifying human cells inside the body to repair disease-causing mutations — including, perhaps, the mutations behind Duchenne muscular dystrophy, the focus of Charles Gersbach’s research. Bosley says that the company will begin announcing targets over the course of 2015 as its priorities take shape.
“We’re still at least a couple years from the clinic,” she adds. “We want to advance these a little further, and have more data to share, before we start talking about specific programs.”