We’re nearly ready to use CRISPR to target far more diseases

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James Cavallini/Science Photo Library

The race is on to edit the DNA in our body to fight or prevent disease. Promising results from animal studies targeting the liver, muscles and the brain suggest that the CRISPR genome-editing method could revolutionise medicine, allowing us to treat or even cure a huge range of disorders.

The CRISPR genome-editing method was only developed in 2012, but it is proving so powerful and effective that around 20 trials in humans have already begun or will soon. Almost all of these involve removing cells from an individual’s body, editing their DNA and then putting them back into the body.

This approach has immense promise, for instance, it is being used to alter immune cells to make them better at killing cancers. It’s relatively easy to remove immune cells or blood stem cells, edit them, and then return them to the body, but this isn’t possible with most bodily tissues.

So editing cells inside the body would allow us to treat far more conditions – from genetic disorders to high cholesterol – and would also be cheaper than growing and editing cells outside the body. What diseases could be treated this way? “Absolutely everything,” says Irina Conboy of the University of California, Berkeley.

Liver disease

The big challenge is delivering the CRISPR machinery to tissues inside the body. Editing genes with CRISPR requires at least two components: a protein that cuts DNA and a piece of RNA that guides it to the precise DNA site to make the cut.

Proteins and RNAs are enormous molecules compared with conventional drugs. It’s hard to get them inside cells, and they don’t usually survive in the bloodstream, either.

But biologists have been working on delivering big molecules to cells for decades and are now adapting various methods for genome editing. Intellia Therapeutics of Cambridge, Massachusetts, for instance, is using fatty particles to deliver the CRISPR components to livers.

One aim is to treat a rare genetic disease called transthyretin amyloidosis, caused by excessive production of the TTR protein. Last week, the company reported that it managed to disable the TTR gene in the livers of mice, reducing levels of the protein by 97 per cent with no signs of any ill effects.

Intellia is also working on a cure for hepatitis B, which infects 250 million people worldwide. The virus can be difficult to eliminate because viral DNA can linger in liver cells. CRISPR can destroy this DNA.

The liver is the easiest organ to deliver fatty particles to because it filters the blood. Anything injected into the blood supply is likely to reach the organ. Conboy’s team has managed something more difficult: they have treated the muscle-wasting disease muscular dystrophy in mice by injecting gold nanoparticles carrying the CRISPR components directly into muscle.

Muscular dystrophy

What’s more, Conboy’s team actually fixed the faulty gene rather than simply disabling it, as Intellia did. Repairing genes is much harder than disabling them. It only worked in 5 per cent of muscle cells, but that was enough to boost muscle strength. And Conboy thinks the proportion of repaired cells could be increased by repeated injections of the gold nanoparticles, although her group has not yet shown this.

“I think this delivery method is fantastic for certain applications,” says Jeffrey Chamberlain at the University of Washington. However, to treat disorders such as muscular dystrophy, muscles all around the body – including the heart – need to be edited. They cannot all be injected directly, so the group hopes to find a way to get the gold nanoparticles into tissues throughout the body.

Chamberlain has been able to edit tissues all over the body using viruses. Earlier this year, his team successfully treated muscular dystrophy in mice by injecting them with an adeno-associated virus carrying DNA coding for the CRISPR components.

Avoiding errors

But there is a big safety issue with viral delivery. If the cutting protein is added to cells, as in the gold nanoparticle method, it soon breaks down. But the viral method involves inserting the DNA for the protein into cells instead, which means the cutting protein keeps being made for weeks after treatment. This greatly increases the chance of DNA also being cut in the wrong place, says Chamberlain.

Already, though, Nicole Deglon of Lausanne University Hospital in Switzerland and colleagues have developed a way to prevent the cutting protein lingering for too long when viruses are used for delivery. Their “kamikaze” CRISPR system not only disables the target gene, it also disables the gene for the cutting protein after a short delay.

Last month, her team showed that this system reduces off-target effects in a mouse study targeting the gene that causes Huntington’s disease. What’s more, they managed to disable the gene in 65 per cent of cells in the key area of the animals’ brains. “I was amazed to see how efficient it was,” says Deglon.

Altogether, a range of methods for delivering CRISPR are showing promise, suggesting the technique’s potential for treating some of our most difficult diseases could soon be realised. It’s impossible to say how soon trials in humans will begin, says Deglon. But the field is advancing so rapidly that it may not be that long. “It’s going faster and faster,” she says.