A new type of gene therapy allows scientists to fix DNA defects directly. That’s a potentially revolutionary improvement on present gene therapy techniques, which introduce working genes to cells — but not into the genetic library itself.
“This is a major leap of the technology,” says John Rossi, a molecular geneticist at the Beckman Research Institute of City of Hope in Duarte, Calif.
Working with newborn mice, researchers led by Katherine High at the Children’s Hospital of Philadelphia found that molecular editors called zinc finger nucleases can correct a genetic mutation that leads to the blood-clotting disorder hemophilia. Fixing a mistake in the gene for blood coagulation factor IX allowed the animals to make about 3 percent to 7 percent of normal levels of the protein, High and her colleagues report online June 26 in Nature. Even such modest increases are therapeutically meaningful, High says. People who make about 5 percent of normal levels of the clotting factor have mild cases of hemophilia.
“I always say that someone with mild hemophilia can play on the college tennis team, but they cannot play on the football team,” says High, a Howard Hughes Medical Institute investigator. By contrast, a person with severe hemophilia may develop bleeding in the knee just by sitting in a chair.
Traditional gene therapy uses viruses to deliver healthy copies of genes into cells. But because the viruses don’t insert themselves into the cell’s DNA, that sort of gene replacement therapy is not a permanent solution, Rossi says.
The new method repairs defective genes using molecules called zinc finger nucleases. These molecules are designed by researchers to recognize a particular gene and then, working in pairs, make a cut in the DNA. The cell’s repair machinery takes over, repairing the break and the typo using a healthy copy of the gene inserted by the researchers as a template.
Zinc finger nucleases have edited mistakes out of cells grown in the laboratory, but no one had previously reported success with correcting typos in an animal. Refinements to the technique must still be made before it could be used in patients, says High. The researchers don’t yet know whether typos can be corrected in adult mice or in larger animals such as dogs and people. And the editing system doesn’t fix the mistakes in many cells, so the researchers would like to boost the correction rate. If the process can be optimized it may provide a way to cure many different genetic diseases, she says.
Ultimately, gene repair might be the best choice for treating genetic diseases, but traditional gene therapy still has its place, High says. “I see no reason to put gene replacement therapy on hold while you try to refine this.”