Gene Editing Treats Disease In A Living Animal For The First Time

Surface of the AAV-2 serotype of the adeno-associated virus (AAV)

In a landmark study, researchers have used gene editing system CRISPR-Cas9 to treat a model of Duchenne muscular dystrophy in mice

Proof of concept for future human treatment

While safety is still a concern, the use of gene editing methods to treat disease in adult patients isn’t controversial. Altering embryos is entirely different to treating an adult, predominantly as the implications are profound and an embryo obviously cannot give permission. 

The majority of experiments utilising the CRISPR system have been ‘in vitro’, which means in cells taken and grown independently in a laboratory. This allows you to carefully monitor results and more easily deliver material into a cell. Treating a living animal is far more tricky, as you require a delivery system that can infect enough of the body to have an effect. While you might think viruses are adept at doing this, many specifically target certain cell types and are inappropriate for wide-scale gene editing. 

“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. 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”

What did the researchers do?

Duchenne muscular dystrophy, DMD,is a rare, crippling disease that affects around 1 in 5000 males. Various mutations lead to an inability to produce functional dystrophin – a key protein that connects muscle fibres to surround tissue. Without it the muscles fall apart over time, and victims rarely make it past 30.

For mice with a debilitating mutation leading to a model of DMD, researchers created a CRISPR-Cas9 system targeted to this sequence. They then encased it within a viral vector called an adeno-associated virus, or AAV. Injecting this into the mice, the virus delivered the system inside cells and it cut out the faulty sequence of DNA. Snipping out a small section of DNA in this manner leads the cell to undergo natural repair mechanisms which ‘stitch’ the gene back together in a shorter manner. In this experiment, it led to a shorter but crucially functional gene. 

The team first injected the mixture directly into the leg muscles of the mice, which produced a significant improvement in function. Dystrophin expression was being restored. They then injected it into the bloodstream and saw a partial improvement in a number of muscles across the body – including the heart which is a problem area in DMD. While the distribution was not perfect and could be more effective, it’s a great step and proves the strategy could one day be a viable one. 

More work needs to be done on different viral vectors, as many are specifically targeted to different areas of the body like cardiac tissue for example. In the future multiple viruses may be used to deliver a gene editing package across the body if required. 

“There is still a significant amount of work to do to translate this to a human therapy and demonstrate safety. 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.”

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