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A new way of making gene-modified cells take over the liver could help researchers treat inherited liver diseases.

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How a liver-damaging drug may give a boost to gene therapy

Researchers who want to treat diseases by ferrying a gene into cells often face the hurdle of safely introducing the DNA into enough of them to make a difference. Now, scientists have come up with a novel way to make gene-modified cells in the liver take over much of that organ: They cripple the unmodified cells. This seemingly risky strategy, which relies on the liver’s exceptional regenerative skills, has passed its first test in mice. If equally successful in people, it could be a boon for treating many inherited diseases involving the liver.

“This is very much proof of concept. The authors [of the new study] would be first to admit it still has a way to go, but it’s a very exciting step in my view,” says Ian Alexander of the University of Sydney in Australia, who works on gene therapy for childhood liver diseases.

Gene therapy is showing promise for several rare diseases, including hemophilia B, in which people lack a livermade protein called factor IX that helps blood clot. Some researchers and companies are currently using a so-called vector, the harmless adeno-associated virus (AAV), to carry into liver cells a loop of DNA with a working copy of the gene for factor IX.

But the treatment has limitations. So far, it hasn’t given hemophilia B patients enough factor IX to completely avoid bleeding episodes—they need about 12% of normal levels, but get half or less with the therapy. And those treated with higher doses sometimes need a steroid drug to counter an immune response to the virus. For many other liver diseases, a similar AAV gene therapy would not modify enough cells, or sustain high enough activity of the new genes, to produce the needed amount of a protein. And in children, such therapies can lose their efficacy as the liver grows and modified cells lose the loops of foreign DNA.

But the human liver’s ability to regenerate offers another strategy. Remove three-quarters, and it will quickly renew itself. Knowing of this bounce-back ability, Sean Nygaard and others in the lab of liver gene therapy researcher Markus Grompe at Oregon Health & Science University in Portland and collaborators at Stanford University in Palo Alto, California, sought to boost production of the foreign gene by giving the modified liver cells two key changes. First, instead of using the AAV to carry loops of DNA into the cell, they designed an AAV to integrate the human factor IX gene into a cell chromosome, near another gene that drove its expression, so that foreign DNA would not be lost as cells divided. The AAV also carried DNA coding for a short strand of RNA that blocks an enzyme that makes liver cells suffer DNA damage and stop dividing when exposed to a drug called CEHPOBA.

In healthy, newborn mice that received an AAV injection in the liver followed by daily injections of CEHPOBA for 4 weeks, the modified liver cells multiplied to replace the disabled ones. As this happened, the mice’s blood levels of human factor IX rose well above the level a patient with hemophilia B would need—from 10- to 30-fold higher than in mice that got the gene therapy but no CEHPOBA, the team reports today in Science Translational Medicine. Depending on the liver disease, by adjusting the doses of CEHPOBA, Grompe says, “you could dial in how much factor IX [or other protein] you wanted.”

But what about the dangers of using a drug to deliberately injure liver cells? Grompe says that is not as risky as it sounds because babies are sometimes born with a condition that mimics the liver-damaging effects of the CEHPOBA drug. Yet they can fully recover if treated. “We have the natural history of what happens to these patients as an argument to say you could do this,” Grompe says. And although CEHPOBA is not an approved drug, his team thinks it can achieve the same results using a RNA that confers resistance to a common drug that is toxic to the liver, such as the painkiller acetaminophen.

Kathy High, president of Spark Therapeutics, a gene therapy company in Philadelphia, Pennsylvania, calls the new strategy “clever,” but she’s wary of injuring any liver cells deliberately. Her company is working on an improved AAV treatment that at low doses has given three hemophilia B patients up to 30% of the factor IX activity of healthy people. "There are other ways to do this," she suggests. Still, she and Alexander say it’s wise to tackle the problem from many angles because it’s hard to predict which will work best in people. “My experience over many years is that trying to work on multiple different strategies is usually a good thing,” High says.