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that boosting fetal beta-globin is attractive because it only requires a knockout. Martin says he and his colleagues are working on that, too, but it “isn’t ready for primetime.”
One caveat of the replacement work is related to sample size. Because stem cells from sickle cell patients are hard to obtain, many of the cells the researchers used were drawn from healthy donors. With the healthy cells, the researchers deployed the same CRISPR-Cas9 tools to insert the sickle cell mutation, a sort of mirror image of the procedure that fixed the mutation in sickle stem cells. What worked going in one direction should work going in the other direction, Martin says, but the researchers will need to reproduce the experiment in larger batches of sickle stem cells drawn from patients to feel more comfortable.
Now they need to raise money for more mouse studies. Another task in the next set of experiments is to watch for long-term safety problems. CRISPR-Cas9 uses molecular scissors guided by a tiny piece of code to match up and snip the right sequence of DNA. But a snip in the wrong place could theoretically lead to an unwanted mutation and to cancer. Some working with CRISPR feel that such “off target effects,” if rare, would likely be checked by the body’s own safeguards. There have been no red flags so far, but the Children’s-IGI-Utah group will watch what happens in their mice over a longer period of time. Jacob Corn, coauthor of the paper and scientific director of the Innovative Genomics Initiative, told me last year that the safety risks of gene editing “should keep everyone in the hematopoietic field up at night.”
Because sickle cell is for some people a manageable disease, the safety of a genetic fix will be a big question with regulators. It’s one thing to green light a drug that might cause cancer when it’s treating cancer patients with no other recourse; it’s another when patients could have decades of life remaining.
“It’s something we’re grappling with,” says Martin. “How far do you need to go to demonstrate safety?”
[The original version of this story said that Children’s Hospital Oakland led the research team, which is not the case..]
Image of sickled red blood cells courtesy of Scooter DMU via Creative Commons.