Nature has the story of an international team led by Portland-based reproductive biologist Shoukhrat Mitalipov, who used CRISPR gene-editing to erase a potentially fatal heart ailment in dozens of embryos:
The researchers targeted a mutation in a gene called MYBPC3. Such mutations cause the heart muscle to thicken — a condition known as hypertrophic cardiomyopathy that is the leading cause of sudden death in young athletes. The mutation is dominant, meaning that a child need inherit only one copy of the mutated gene to experience its effects.
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The team also tackled two safety hurdles that had clouded discussions about applying CRISPR–Cas9 to gene therapy in humans: the risk of making additional, unwanted genetic changes (called off-target mutations) and the risk of generating mosaics — in which different cells in the embryo contain different genetic sequences. The researchers say that they have found no evidence of off-target genetic changes, and generated only a single mosaic in an experiment involving 58 embryos.
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Mitalipov’s team took several steps to improve the safety of the technique. The CRISPR system requires an enzyme called Cas9, which cuts the genome at a site targeted by an RNA guide molecule. Typically, researchers wishing to edit a genome will insert DNA encoding CRISPR components into cells, and then rely on the cells’ machinery to generate the necessary proteins and RNA. But Mitalipov’s team instead injected the Cas9 protein itself, bound to its guide RNA, directly into the cells.
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[S]ays genome engineer Jin-Soo Kim of the Institute for Basic Science in Daejeon, South Korea, and a co-author on the study. “Cas9 is rapidly degraded,” he says. “There is little time for off-target mutations to accumulate.”
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In an experiment Mitalipov’s group performed in 58 human embryos fertilized with sperm carrying the MYBPC3 mutation, 42 were successfully edited to contain two normal copies of the MYBPC3 gene. Only one was a mosaic. By comparison, the team found that 13 of 54 treated embryos were mosaics when the CRISPR–Cas9 machinery was injected 18 hours after fertilization.
The low rate of mosaics and the unusually high efficiency of gene editing make the study stand out, says stem-cell biologist Fredrik Lanner of the Karolinska Institute in Stockholm, who co-authored a commentary accompanying the article. Additional testing is needed to show that the low rate of mosaics holds true for other gene-editing targets, but for now, he says, “it’s a huge step in that direction”.
Lanner is also editing genes in human embryos, as a way of learning more about developmental biology. But he notes that in Sweden, it would be illegal for him to create embryos solely for the sake of research. Instead, he must use surplus embryos from fertility clinics (created using eggs that have already been fertilized), putting the kind of study that Mitalipov’s team did — in which CRISPR–Cas9 machinery is introduced at the same time as sperm — out of reach.
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Had to pause for moment when I realized HCM was the thing they were working on. I’ve got that. A non-fatal version… so far. Still. Weird to see it there.
Anyway, there’s plenty more to read on this from Mr. Rowan Jacobsen.