For the first time, scientists have used CRISPR gene editing to successfully treat a genetic disease inside a fully developed living mammal. CRISPR editing is a process whereby scientists can effectively rewrite the genetic code of an organism by cutting out and replacing individual components of DNA.
In this study, researchers in the US used CRISPR to treat an adult mouse model of Duchenne muscular dystrophy, delivering the gene-editing system directly to affected tissues by way of a non-pathogenic virus called adeno-associated virus, or AAV.
"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 Charles Gersbach, a biomedical engineer at Duke University. "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."
Duchenne muscular dystrophy (DMD) is a rare form of muscular dystrophy that affects about one in 5,000 human males. The disease, caused by a genetic mutation, impairs the body's ability to produce dystrophin, a protein chain that connects muscle fibre to surrounding tissue. Without the support of the protein, muscles in the body begin to deteriorate.
Most men affected by DMD are wheelchair-bound by the age of 10, and many do not live beyond their 20s or 30s.
While the researchers had previously used electrical jolts to deliver CRISPR in cultured cells, such an approach isn't possible with a living patient. Fortunately, there are other means of getting in close.
"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 Chris Nelson, one of the researchers. "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."
To repurpose viruses as delivery vehicles for gene therapy, researchers take out any harmful or replicating genes in a virus and insert the therapeutic genes they want to apply to the patient's tissue.
In this study, the researchers performed the technique on a mouse model with a debilitating mutation on one of the protein-coding regions (called exons) of the dystrophin gene, which render the gene unable to produce the protein.
The team programmed the CRISPR system to cut out this dysfunctional exon, which prompts the body's natural repair system to stitch the remaining gene back together, creating a shortened, but now functional, version of the gene.
The researchers first experimented with the technique by delivering the therapy directly to a leg muscle in an adult mouse. Once they saw that the leg muscle had been restored in strength thanks to its new supply of functional dystrophin, they injected the CRISPR/AAV combination into the animal's bloodstream. This resulted in partial dystrophin corrections in other muscles throughout the body, including the heart – which is significant, as heart failure is a common cause of death for patients with DMD.
While it's early days, and there's a long road ahead in getting this kind of approach to work on fixing genetic diseases in living people, the researchers involved believe their findings, which are reported in Science, will indeed help get us to that point.
"There is still a significant amount of work to do to translate this to a human therapy and demonstrate safety," said Gersbach. "But these results coming from our first experiments are very exciting. From here, we'll be optimising 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."
For more on CRISPR and how it works, check out this following video: