science fiction not long ago—an alteration of someone’s DNA that, by the way, is irreversible—can proceed safely into human testing? With its zinc fingers, Sangamo has paved the way, he says. It has a treatment for HIV in a Phase 2 trial, and in recent months received clearance to start trials in hemophilia B and the rare mucopolysaccharidosis Type I.
“Sangamo has demonstrated that you can work with the FDA to come up with a body of evidence” that the gene editing machinery isn’t going astray once inside the body and cutting DNA in the wrong spots, said Leonard. There’s a debate right now—perhaps “raging” is too strong a word, but certainly passionate—whether the field has the right tools to detect these off-target cuts, and what fine-grained level of detection is necessary to make sure CRISPR-Cas9 is safe. Keith Joung, a pathologist and DNA researcher at Massachusetts General Hospital in Boston and cofounder of Editas, is developing one of those detection systems; he told Xconomy earlier this year that even more sensitive detection is necessary.
That kind of talk “drives me up the wall,” Crispr Therapeutics CEO Novak told me the week after I spoke with Joung. It loses sight of the “so what” question, said Novak: Not how many cuts are taking place, but are they creating a real risk of cancer? Or are they cuts that our cells could deal with on an everyday basis?
The debate is important because a previous generation of gene therapy was brought to a halt by treatments gone awry. In France and the U.K. last decade, experimental treatments to cure X-linked severe combined immune deficiency disorder (the “bubble boy disease”) triggered leukemia in at least five children, and in 1999, teenager Jesse Gelsinger died while being treated for a genetic liver disease in a trial at the University of Pennsylvania. Any similar catastrophes with gene editing, whether CRISPR-Cas9 or other systems, could be devastating to the whole field, especially as the public begins to grapple with the profound potential of these new biological tools.
With one eye on safety, Intellia has decided to send CRISPR-Cas9 into the liver by wrapping it, essentially, in tiny droplets of fat. (The technical term is lipid nanoparticles, or LNPs.) There are other delivery vehicles available, such as AAV modified viruses, but Intellia has chosen LNPs, even though other companies using them to deliver experimental medicines to patients have had problems. “It’s fair to say that LNPs in the clinic have had some liabilities,” says David Morrissey, Intellia’s chief technology officer, who previously ran an RNA group at Novartis. He knows LNPs intimately. The ones he helped develop at Novartis are now in Intellia’s hands. Many drug developers have used LNPs to try to deliver short RNA strands, similar to the CRISPR-Cas9 guides, into cells. Their function can be to interrupt production of disease-causing proteins, either coming from a defective gene or an invading virus. Or the RNA strands can help cells produce beneficial proteins. None of these RNA drugs has been approved.
Injected over and over again, the LNPs might build up in cells and cause damage. But with a CRISPR-Cas9 therapy, which if successful would require one or at most a few doses, Intellia is betting it can avoid safety problems while reaping the advantages of LNPs, like a lower manufacturing cost than other drug delivery vehicles.
Although Intellia and Editas gave fair warning in their regulatory filings about the risk of ethical concerns blunting their business, CRISPR-Cas9 drug development is by and large separate from the “designer baby” fears that turned CRISPR-Cas9 into a headline last year and spurred an international summit of top scientists.
Intellia, its peers, and collaborators are working on editing somatic, or, mature cells, not the germline of eggs, sperm, and embryos that would allow changes to pass down to future generations. Yet with human testing of CRISPR-Cas9 therapies likely a matter of when, not if, there are other ethical questions to ponder. For example, what if someone tests positive for an allele—a version of a gene—that indicates a high risk of early Alzheimer’s or aggressive breast cancer, but the person shows no symptoms of the disease? If the risk is high but not 100 percent, should that gene be edited out? Who should pay for the treatment?
If those situations arise, it’s possible that drug access and pricing, which many people in the U.S. are eager to overhaul, will look radically different.
But those are distant horizons. Companies like Intellia first must show that the life-changing medicines they’re working on are not as far out as once imagined. Asking the public to support that work, as Intellia will do next week, is just one step toward that goal.
Image courtesy of Ivydawned via a Creative Commons license.
