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31st March 2014

New gene-editing technique cures a rare liver disorder

The first evidence that CRISPR can reverse a disease in living animals has been demonstrated. Using this new gene-editing technique, MIT researchers cured mice of a rare liver disorder.


gene editing
Illustration: Christine Daniloff/MIT


CRISPR is a revolutionary new technique for editing DNA. It is much faster and more accurate than previous methods, enables many genes to be modified at once, and can reduce the times needed for animal studies from months to weeks. Gene therapy often involves using modified viruses that insert DNA at random places on the genome – a haphazard and risky process that is unsuitable for many patients. With CRISPR, however, extreme precision allows detailed alterations of any specific position on the genome, without introducing unintended mutations or flaws. Last year, it was described by Nobel-winning scientist Craig Mello as "jaw-dropping", "a real game-changer" and "a tremendous breakthrough with huge implications for molecular genetics."

Now, researchers at the Massachusetts Institute of Technology (MIT) have used CRISPR to snip out faulty DNA in mice and replace it with the correct sequence – curing them of a rare liver disorder. This new study, published yesterday in Nature Biotechnology, offers the first evidence that CRISPR is able to reverse disease symptoms in living animals.

Professor Daniel G. Anderson, senior author of the paper: "What's exciting about this approach is that we can actually correct a defective gene in a living adult animal."

When bacteria come under attack from viral infection, they rely on a type of cellular machinery to defend themselves. Researchers have copied this system to create gene-editing complexes. This includes a DNA-cutting enzyme called Cas9, which is bound to a short RNA guide strand – programmed to bind to a specific genome sequence and tell Cas9 where to make its cut. At the same time, the researchers also deliver a DNA template strand. When the cell repairs the damage produced by Cas9, it copies from this template, introducing new genetic material into the genome.

This method holds potential for treating many genetic disorders in humans, say the researchers. Other gene-editing systems based on DNA-slicing enzymes have been created in the past – but using those complexes, it is much harder and more expensive to make a nuclease that's specific to your target of interest.

"The CRISPR system is very easy to configure and customise," says Anderson.

In experiments with adult mice carrying a mutated form of the FAH enzyme, researchers delivered RNA guide strands and the gene for Cas9, along with a 199-nucleotide DNA template for the correct sequence. The healthy gene was inserted in about 0.4 percent of hepatocytes – the cells that make up most of the liver. Over the next 30 days, those healthy cells began to spread and replace diseased liver cells, eventually accounting for one-third of all hepatocytes. This was enough to cure the disease, allowing the mice to survive after being taken off medication.

"We can do a one-time treatment and totally reverse the condition," says Hao Yin, a postdoc at the Koch Institute and one of the lead authors of the Nature Biotechnology paper.

"This work is an exciting first step to using modern gene-editing tools to correct devastating genetic diseases for which there are currently no options for affected patients," says Charles Gersbach at Duke University, who was not part of the research team.

To deliver the CRISPR components, the researchers employed a technique known as high-pressure injection, which uses a high-powered syringe to rapidly discharge material into a vein. This approach delivers material successfully to liver cells – but Anderson envisions that better delivery approaches are possible. His lab is now working on methods that may be safer and more efficient – including targeted nanoparticles.

In the last year, thousands of research labs around the world have started using the CRISPR system to create their own genetically modified cell lines. IVF doctors believe it could be used to prevent inherited diseases in families by changing an embryo's DNA before implantation into the womb. In addition to medical cures, CRISPR may accelerate the development of GM crops and livestock.


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