New direction for gene therapy

Written byAlla Katsnelson

| 2 min read

Researchers have identified a new strategy for circumventing the safety problems that have plagued linkurl:gene therapy;http://www.the-scientist.com/article/display/23064/ according to a linkurl:study;http://www.cell.com/content/article/abstract?uid=PIIS0092867408001165 published online in Cell today. The study reports that adenovirus, a common vector for delivering gene therapy, transfects liver cells by a different mechanism than previously thought. That mechanism offers a new target for modifying the viral vector to make it safe for clinical use, said linkurl:Mark Kay;http://kaylab.stanford.edu/Pages/marknew.html of Stanford University, who was not involved in the research. Researchers have had some success using adenovirus as a vector to deliver genes into specific locations, such as linkurl:a solid tumor.;http://www.the-scientist.com/article/display/15449/ But when it's injected intravenously, the virus accumulates in the liver instead of circulating in the body, raising the risk of toxicity and hampering transfection of other cell types. Adenovirus consists of three major proteins - fiber, penton and hexon. Based on earlier work, most researchers held that the main mechanism of viral transduction was the fiber protein's interaction with a receptor on the target cell. But attempts to mutate the fiber protein didn't block the virus's accumulation in the liver in vivo. "At the end of the day, people have been working on the wrong proteins here," linkurl:Andrew Baker;http://www.bscr.org/profile_abaker.html of the University of Glasgow, who led the current research, told The Scientist. "This is why all these fiber-modified viruses still end up transducing the liver." Baker's group focused instead on the hexon protein. The researchers mutated the protein, disabling its ability to interact with a blood clotting enzyme, Factor X. Those mutations, and pharmacological blockade of the interaction, did indeed block gene transfer, suggesting that the virus enters liver cells via the interaction of the hexon protein and Factor X. Fiber-mediated transduction "certainly happens when you inject virus in, say, muscle, and also in cell culture," Baker said. "But it's when you inject into the blood stream that this mechanism takes over, and it's critical." "I actually heard about this [mechanism] a number of years ago," said Kay. "Honestly, I wasn't sure I believed it." But the results here are convincing, he said, and help resolve conflicting data in the field. "Now that we've found the mechanism that a virus uses," Baker said, "we can modify that process either by drugs or by genetically engineering the virus, to improve uptake into other cell types."

New direction for gene therapy

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