CRISPR-Cas9 patents and some subsequent work. “Certainly, if there is not a strong belief that a given therapy has the potential to be effective for a given patient,” Bosley says, “it would not be appropriate to include that patient in a trial.”
Bosley did not say specifically whether a whole genome sequence of every potential patient in a clinical study, as Zhang and Scott suggest, is part of Editas’s preclinical work. Editas recently announced that its lead program, a treatment for a rare genetic eye disease, would likely enter clinical studies in 2018 instead of 2017.
Just as a conventional drug developer will often start with a vast library of chemical compounds that might be effective against a biological target, CRISPR companies start with thousands of versions of RNA guides. Those guides are matched up against an array of potential off-target sites, says CRISPR Therapeutics (NASDAQ: [[ticker:CRSP]]) CEO Rodger Novak. If one version of a guide appears to cut at an off-target site, the guide is tossed out, says Novak. CRISPR Therapeutics uses whole genome sequencing in its preclinical work, but not necessarily for each potential patient in a clinical study.
Novak calls the Zhang and Scott paper “interesting… but not necessarily surprising or a fundamental change as to how we look at targeting specific genes.”
CRISPR Therapeutics has entered into collaborations with Bayer HealthCare and Vertex Pharmaceuticals (NASDAQ: [[ticker:VRTX]]). With Vertex, it might push its first program for the blood disorder beta-thalassemia into clinical studies next year.
In the case of CRISPR, the critical tool in question is the RNA guide that can be customized to match a string of the patient’s DNA, usually about 20 nucleotides long. The guide and scissors travel into the cell’s nucleus together. When the guide finds its match in, say, a string of DNA that is causing disease, the scissors make their cut. CRISPR is also capable of replacing a gene—a cut-and-paste operation, or “correction,” instead of just a cut, or a “knockout”—and Zhang says his recommendations for better, safer CRISPR therapeutics apply to “various modes of gene correction.”
Correcting genes in humans, if at all possible, will be farther down the road, however. The nearer-term goals for CRISPR drug companies are medicines that simply knock out a disease-causing gene, with no replacement necessary.
The new paper comes a few days after a report that researchers at the Oregon Health and Science University used CRISPR to alter genes in human embryos, which would be a first in the U.S. Their work, which used embryos that were never meant to be implanted, has not been published; MIT Technology Review broke the story, citing at least one researcher associated with the work.
The possibility of editing human embryos, sperm, or eggs—together known as the germline, because the altered traits could be passed down through generations—is a far more controversial topic than the one-off, or “somatic” changes that companies and researchers are racing to turn into human therapies. Germline editing is likely necessary to address some diseases. But the ethical roadblocks, including the specter of making aesthetic and other non-medical changes, will keep a lid on real-world applications, at least in the U.S., for some time. Doudna and other prominent scientists called in 2015 for a moratorium on germline editing aimed at in vitro fertilization and other applications.
Zhang photo by Keith Spiro.
