Researchers who want to treat illnesses carrying a gene into cells are often faced with the obstacle the introduction of DNA into them securely enough to make a difference. Now scientists have developed a new way to genetically modified cells in the liver take over much of this body: They paralyze the unmodified cells. This strategy seems risky, based on the exceptional regenerative powers of the liver, has passed its first test in mice. If so successful in people, it could be a boon for the treatment of many inherited diseases involving the liver.
"This is very good proof of concept. The authors [of the new study] would be the first to admit he still has a way to go, but it is a very exciting step in my opinion," said Ian Alexander of the University of Sydney in Australia, working on gene therapy for liver disease in children.
Gene therapy shows promise for several rare diseases including hemophilia B, in which people do not have a protein called factor IX livermade that helps blood clot. Some researchers and companies currently use a so-called vector, the harmless adeno-associated virus (AAV), to transport in liver cells a DNA loop with a working copy of the factor IX gene.
But the treatment has its limits. So far it has not given patients with hemophilia B enough factor IX to completely prevent bleeding episodes, they need about 12% of normal levels, but get half or less with therapy. And those treated with higher doses sometimes need a steroid medication to counter an immune response to the virus. For many other liver diseases, a similar AAV gene therapy would not change enough cells, or maintain a sufficiently high activity of the new genes to produce the necessary amount of protein. And in children, these therapies may lose their effectiveness as the liver and the modified cells develops lose the loops of the foreign DNA.
But the human liver's ability to regenerate offers another strategy. Remove three-quarters, and it will be renewed quickly. Knowing this ability to rebound, Sean Nygaard and others in the laboratory of gene therapy researcher Markus Grompe liver Oregon Health & Science University in Portland and colleagues at Stanford University in Palo Alto, California, sought to stimulate the production of the foreign gene by giving liver cells modified two important changes. First, instead of using AAV to produce DNA loops in the cell, they conceived an AAV to integrate into the human factor IX gene into a chromosome of the cell, close to another gene which leads expression, so that the foreign DNA is not lost as cells divided. AAV also carried DNA encoding a short strand of RNA that blocks an enzyme that makes liver cells undergo DNA damage and stop dividing when exposed to a drug called CEHPOBA.
in mice healthy newborns who received an injection of AAV in the liver, followed by daily injections of CEHPOBA for 4 weeks, modified liver cells multiplied to replace those with disabilities. As it happened, the mice blood levels of human factor IX has increased well above the level of a patient with hemophilia B would need 10 to 30-fold higher than in mice that received therapy gene, but not CEHPOBA, reports the team today science Translational Medicine . Depending on liver disease, adjusting doses of CEHPOBA, Grompe said, "you can dial in how much the factor IX [or other protein] you wanted."
But the dangers of using a drug to deliberately injure the liver cells? Grompe said that is not as risky as it sounds because babies are sometimes born with a condition that mimics harmful liver effects of the drug CEHPOBA. Still, they can completely recover if treated. "We have the natural history of what happens to these patients as an argument to say you can do it," said Grompe. And although CEHPOBA is not an approved drug, his team thinks he can get the same results using RNA that confers resistance to a common drug that is toxic to the liver, as the analgesic acetaminophen.
Kathy High, President of Spark Therapeutics, a gene therapy company in Philadelphia, Pennsylvania, called the new "smart" strategy, but it is wary of hurting liver cells deliberately. His company is working on an improved AAV treatment at low doses gave three patients with hemophilia B to 30% of the activity factor IX of healthy people. "There are other ways to do it," she suggests. Yet she and Alexander say it is wise to approach the problem from many angles, because it is difficult to predict what will work best in people. "My experience over many years is that of trying to work on several different strategies is generally a good thing," said High.
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