PHILADELPHIA -- University of Pennsylvania researchers have snipped out a single gene in patients' immune cells to make them partly resistant to infection with HIV, the virus that causes AIDS.
The study, in this week's New England Journal of Medicine, bolsters hope for controlling HIV without daily antiviral drugs -- a so-called functional cure.
But even more important, as the first paper to report the modification of an exact spot in human DNA, it marks the arrival of the age of gene editing.
The researchers' editing tool, developed by Sangamo BioSciences of Richmond, Calif., was made of natural proteins that recognize specific DNA sequences. These "zinc finger nucleases" can be used like molecular scissors to introduce intentional genetic mutations.
Until now, gene therapy has relied on disabled viruses to carry and dump genes somewhat randomly into a cell's DNA.
"The ability to edit the human genome has been a prayer ever since we first understood that genes control biology," said Sangamo CEO Edward Lanphier, who founded the company in 1995. "But we've moved beyond the concept of gene replacement, which was the idea behind gene therapy. Gene editing is much safer and more effective."
Eminent AIDS researcher Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said, "I think this is an important step in the right direction, not only for HIV, but for other diseases."
Indeed, Sangamo is working on zinc finger-based approaches to treat and possibly cure hemophilia, Huntington's disease and sickle-cell anemia -- diseases caused by a single defective gene. The firm also supplies ready-made and custom-made zinc finger proteins to scientists around the world.
"And further progress can be expected," wrote Stanford University researchers Mark A. Kay and Bruce D. Walker in an editorial accompanying the Penn study. "In the past few years there has been an explosion in new 'genome editing' technology."
The Penn study -- led by gene-therapy pioneer Carl June and underwritten with federal and Sangamo funding -- built on the observation that some people are naturally invulnerable to HIV infection because of genetic variations. When they do get infected, their progression to AIDS is unusually slow.
One such gene variant keeps T cells -- the disease-fighting blood cells that HIV attacks -- from making a receptor, a sort of doorway, that HIV uses to break in. About 10 percent of Caucasians have inherited one copy of this gene variant, making them resistant to HIV infection. About 1 percent have two copies -- one from each parent -- making these fortunate few immune to HIV.
To artificially confer this invulnerability, Dr. June's team removed T cells from 12 HIV-infected patients who were taking standard antiviral drugs and used zinc fingers to delete the doorway receptor gene. The modified T cells were coaxed to multiply, then each patient received a transfusion of roughly 10 billion.
Zinc finger editing is not perfect -- at least, not yet -- so only about 20 percent of the modified cells actually lacked the doorway receptor gene. To see whether these modified cells might be fighting HIV, the researchers interrupted standard drug therapies for three months in six patients with healthy T cell counts. (The other six patients had suboptimal T cell counts despite standard drugs, so their treatment was not interrupted.)
Blood levels of HIV decreased in four of the patients who suspended treatment, falling to an undetectable level in one man. A single patient had a serious complication, but it was a reaction to the transfusion, not the cells.
Some of the modified T cells were found to concentrate in the patients' guts, where HIV builds a stockpile. Current drugs reduce the ability of HIV to reproduce but can't completely eliminate it from the body because of this reservoir.
"We believe the only effective way to functionally cure HIV is to get the immune system to reduce the reservoir," Mr. Lanphier said.
As the first gene-editing study to be rigorously reviewed and published in a scientific journal, Penn's paper is an automatic landmark.