For the first time ever, scientists have used the CRISPR gene-editing tool to successfully treat a genetic muscle disorder in a living adult mammal. It’s a promising medical breakthrough that could soon lead to human therapies.

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Scientists have struggled to treat Duchenne muscular dystrophy for decades. To date, their efforts have been focused on treating cultured cells in petri dishes, or in trying to get CRISPR/cas9, a powerful DNA cut-and-paste tool, to deliver the repaired copy of the defective genes effectively and safely. Now, using a specially modified virus, researchers from Duke University have confirmed a promising solution using live mouse models. The team’s study appears in the latest edition of Science.

Duchenne muscular dystrophy is a muscle-wasting disease that affects one in 5,000 newborn males. The genetic glitch is on the X chromosome, so girls with two X chromosomes tend to have at least one functioning copy of the gene. Symptoms typically appear between the ages of 3 and 5, after which the disorder progresses quickly. Most boys are unable to walk by the time they’re 12, and they eventually need a respirator to breathe. Life expectancy is between 20 to 30 years.

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The genetic disorder is caused by the absence of dystrophin, a critically important long protein chain that maintains the integrity of muscles. Dystrophin is coded by a gene containing nearly 80 protein-coding regions called exons. If even a single exon is badly mutated, the chain won’t get built. And without dystrophin, muscles slowly deteriorate.

The restored production of dystrophin (light green) in the muscle cells of mice. Credit: C. E. Nelson et al., 2015

The Duke researchers, led by geneticist Chris Nelson, used CRISPR/cas9 to remove the problematic DNA that was preventing the cells from producing dystrophin.

CRISPR, a tool that emerged just three years ago, allows scientists to edit genomes with incredible precision and flexibility. Like a person trying to solve a jigsaw puzzle, the system uses synthetic DNA known as CRISPRs to scan a genome in search of the right spot. A protein called cas9 acts as a pair of scissors to cut through the DNA.

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To deliver these genetic alterations, the Duke researchers used a type of non-pathogenic virus. “A major hurdle for gene editing is delivery. We know what genes need to be fixed for certain diseases, but getting the gene editing tools where they need to go is a huge challenge,” said Nelson in a release. “The best way we have to do it right now is to take advantage of viruses, because they have spent billions of years evolving to figure out how to get their own viral genes into cells.”

For the study, the researchers worked with genetically modified mice that had the debilitating mutation on one of the exons of the dystrophin gene. The scientists programmed the new CRISPR/cas9 system to weed out the dysfunctional exon, leaving the body’s natural repair system to stitch the remaining gene back together. The result was a shortened, but functional, version of the gene.

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In order to reach every muscle, the virus was injected into the bloodstream of the mice. Results showed measurable corrections of muscles throughout the body, including the heart—a particularly important result, considering that heart failure is major cause of death among Duchenne patients.

However, the mice that received the therapy did not do as well as normal mice on muscle tests, so it’s not a cure. That said, the researchers believe there’s plenty of room for improvement, and that upwards of 80-percent of people with DMD could benefit from having a faulty exon removed.

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“There is still a significant amount of work to do to translate this to a human therapy and demonstrate safety,” said Duke researcher Charles A. Gersbach. “But these results coming from our first experiments are very exciting. From here, we’ll be optimizing the delivery system, evaluating the approach in more severe models of DMD, and assessing efficiency and safety in larger animals with the eventual goal of getting into clinical trials.”

Two other teams—all working independently from one another—achieved similar results in their research. These studies were conducted by Eric Olson at the University of Texas Southwestern Medical Center and Amy Wager at Harvard University.

Unlike efforts to modify the germline of embryos, this particular approach can be applied to a living being. This means the genetic changes can be introduced later in life, and they aren’t heritable.

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“Recent discussion about using CRISPR to correct genetic mutations in human embryos has rightfully generated considerable concern regarding the ethical implications of such an approach,” said Gersbach “But using CRISPR to correct genetic mutations in the affected tissues of sick patients is not under debate. These studies show a path where that’s possible, but there’s still a considerable amount of work to do.”

[Duke University, New York Times, Science AAAS]


Email the author at george@gizmodo.com and follow him at @dvorsky. Top image: Dystrophin (light green) is seen in cardiac muscle from normal mice (left), missing in mice with DMD (center), and partially restored in Duchenne mice treated with CRISPR/Cas9 (right). Credit: C. E. Nelson et al., 2015