Gene therapy treats Duchenne muscular dystrophy in mice
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Gene therapy has long struggled with a delivery problem: How do you distribute an edited gene to all of the parts of the body where it needs to go? Now scientists have used the CRISPR genome editing tool in mice to solve that problem, a promising finding on the long path to a human therapy.

Three papers, published Thursday in the journal Science, show that scientists can use CRISPR’s molecular scissors to treat mice that have been genetically modified to have Duchenne muscular dystrophy, a rare and fatal disease. A similar feat had been accomplished previously in a Petri dish with human cells or mouse embryos, but for the new work, scientists injected the therapy into juvenile and adult mice.

“We’re putting CRISPR right into the tissues to do the gene editing. That’s the real breakthrough here,” said Charles Gersbach, associate professor of biomedical engineering at Duke University and the lead investigator on one of the studies.

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A similar endeavor last year, by MIT biologist Daniel Anderson, successfully treated a mouse model of a very rare genetic disorder called hereditary tyrosinemia type I. While Anderson’s study targeted just the liver, however, the new studies treated a disease that affects muscles throughout the body.

“This is really important work in particular for people who are suffering from DMD,” Anderson said of the new studies, in which he was not involved. The mouse studies “show you can have meaningful effects on this really terrible disease.”

“But there’s other work that needs to be done before you’re ready to treat people,” he cautioned.

Duchenne muscular dystrophy, which affects 1 in 3,500 boys in the United States, stems from an error in a gene that produces a protein called dystrophin, which is key for normal muscle function. Without dystrophin, patients’ muscles degenerate, and they have to use wheelchairs by their preteen years and typically die before they turn 30.

Two companies have been racing to get federal approval for the first drug combating Duchenne, amid a strong lobbying push from patient families.

Meanwhile, scientists have faced big hurdles in figuring out how to use CRISPR, which can slice and replace portions of the human genome, to treat the disease. They’ve used CRISPR in single-cell embryos of mice with Duchenne, but that won’t work for humans, because editing human embryos is, for now, considered a big ethical no-no. Scientists have also used CRISPR to edit cells of Duchenne patients in a lab dish, but delivery is difficult: Duchenne affects all of the muscle tissues and the heart, and you can’t take all of those cells out of the body to treat them and put them back in.

The approach published Thursday, instead, directly edits muscle tissue in living mice. Scientists used the adeno-associated virus (AAV) to carry the CRISPR-Cas9 complex into the mouse’s body to snip away one mutated portion of the gene that produces dystrophin.

Unlike in other uses of CRISPR, in this case scientists did not replace the snipped section with anything else: They just left behind a shortened version of the gene, which turned out to be functional.

Gersbach’s team at Duke injected the virus into the leg muscle of an adult mouse model of Duchenne and found that it restored dystrophin and boosted muscle strength. They also injected it into the mouse’s bloodstream and discovered that it repaired and strengthened muscles throughout the body, including in the heart.

That’s an important finding, Gersbach said, because when humans die from Duchenne, “it’s not because the arm or leg muscles get weak — it’s because their hearts give out.”

The other studies, by researchers at the University of Texas and at Harvard, found similar results using an AAV/CRISPR combination in mouse models of Duchenne, which show “that the technology is really strong and reproducible,” Gersbach said.

Gersbach said his lab’s next steps are to improve the efficiency of the delivery, and then test the approach in larger animals, such as dogs or primates, to see if it works “with larger doses, and with genes that are more similar to the human genes.”

Before testing this gene therapy in humans, scientists will have to test its safety. And they’ll have to understand “how the human immune system will react to delivering the CRISPR complex within the body,” Gersbach said.

Gersbach said he can foresee starting human trials in a couple of years if those obstacles are cleared.

Anderson, who cofounded CRISPR Therapeutics to commercialize CRISPR gene therapy, is also thinking about the steps toward a human therapy.

“My overall sense is that these things are going to find uses in people,” he said, “but it’s going to be important for each case to [be] look[ed] at.”

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