ABOUT TEN YEARS ago, British veterinarians discovered an unlucky family of King Charles Spaniels whose male pups sometimes came down with a mysterious set of maladies before their first birthday. They grew clumsy and weak, and they often choked on their own tongues. To blame was a mutation on their X chromosomes, in a gene that codes for a shock-absorbing muscle protein called dystrophin. When researchers at the Royal Veterinary College realized the puppers had a canine version of the most common fatal genetic disease in children—Duchenne muscular dystrophy—they began breeding the sick spaniels with beagles to start a canine colony in the hopes of one day finding a cure.

Today, scientists report they’ve halted the progression of the disease in some of those doggy descendants using the gene editing tool known as Crispr.

In a study published Thursday in Science, a team led by Eric Olson at the University of Texas Southwestern Medical Center used Crispr to successfully modify the DNA of four young dogs, reversing the molecular defect responsible for their muscle wasting disease. DMD isn’t an obvious candidate for Crispr’s find-and-replace function; the dystrophin gene is the largest in the human genome, and there are thousands of different mutations that can all result in the disease. But Olson found a way to target an error-prone hot spot on exon 51, which he figured could, with a single slice, benefit approximately 13 percent of DMD patients.

Building on previous work he had done to correct mutations in mice and human heart cells, Olson teamed up with vets at RVC to test the approach on their beagle colony. The researchers first packed the instructions for the Crispr gene-editing components into a virus with an affinity for muscle cells. Then they injected millions of copies of that virus into four one-month-old dogs—two got the shot directly in the lower leg, and two received an intravenous infusion. After eight weeks, Crispr had restored dystrophin levels in the second group to more than 50 percent of normal in the legs, and more than 90 percent in the heart.

Researchers estimate that restoring 15 percent of the normal levels of dystrophin in a patient would provide a significant, even curative benefit. “We’re certainly in that ballpark with these dogs,” says Olson, who didn’t know what to expect going into the study because no one had ever delivered Crispr body-wide in a large mammal before. His team prepared for the worst—anaphylaxis, liver toxicity, an inflammatory immune response—but in the end they saw no adverse effects. Instead they saw puppies who could play again. “They showed obvious signs of behavioral improvement—running, jumping—it was quite dramatic,” says Olson, who didn’t include those qualitative observations in the paper on account of the small sample size.


In dogs with DMD, you can see the absence of the dystrophin protein.UT SOUTHWESTERN MEDICAL CENTER


In DMD dogs treated with CRISPR, levels of dystrophin are restored.UT SOUTHWESTERN MEDICAL CENTER

The breakthrough effort was backed, in part, by a startup called Exonics, which was cofounded in 2017 by Olson and patient advocacy group CureDuchenne. Headquartered in Cambridge, Exonics has licensed the gene editing technology developed by Olson’s lab and is moving it toward human trials, with the hopes of one day commercializing treatments. The young biotech company got its footing with $2 million from CureDuchenne’s venture arm, and it has since raised more than $40 million from The Column Group.

Via Wired