Gene therapy shows promise in HIV-positive patients

Gene therapy shows promise in HIV-positive patients
By Suzanne Bohan Contra Costa Times
October 07, 2011

WALNUT CREEK, Calif. — A novel chemical editing of a gene strengthened immune systems in HIV-positive men, and one participant even cleared the virus without drugs, scientists recently announced.

“We were stunned,” said Elizabeth Wolffe, a scientist with Sangamo BioSciences in Richmond, Calif., which developed the gene therapy. “It isn’t usual that someone would clear their virus without having medication.”

The gene therapy altered a critical class of immune cells — T cells — the front line in battling the virus. HIV defeats this defense by latching to T cells and destroying them.

The therapy snipped out a gene that enables the virus to attach to T cells, so they could deflect the deadly virus, study results indicate. On its own, the virus exists for less than a day, and it needs the immune cells to survive and multiply. An army of genetically altered T cells deflecting HIV would deplete the virus’s ranks, one researcher said.

The altered immune cells were also replicating, buoying hopes of long-term protection.

Given the small size of the trials — nine men in one and six in the other — researchers tempered their responses to the early results. But scientists say they point to a promising way to clear the virus without the difficult side effects and high cost of a lifetime of antiretroviral medications, which run $15,000 to $20,000 a month. Patients in the trials had only minor and transitory side effects, Sangamo BioSciences reported.

“Do I think we have a cure?” said Dr. Pablo Tebas, a University of Pennsylvania researcher running one of the trials. “No, but I think it’s a very exciting result that points in the direction we need to go. And then maybe we will one day reach that holy grail, not needing antiretroviral therapy.”

Medical advances rely on repeated successful tests of a treatment with large groups of study subjects, and many questions also remain unanswered with the Sangamo trials, including how long the genetically modified cells will last.

The genetically altered T cells retain their typical behavior, racing to attack bodily invaders. During the study, the modified cells traveled where “HIV reservoirs” are known to hide out, such as in the gut, Wolffe said.

It’s these hidden reservoirs that keep T cell counts low for some HIV carriers even when blood levels of the virus are undetectable, as the virus can still destroy T cells from its redoubt.

The findings were presented Sept. 17 and Sept. 18 at a Chicago medical conference.

A man in one of the trials said his low T cell count almost doubled two weeks into it and has remained there.

For the first time in years, Matt Sharp, 55, said he hasn’t picked up an upper respiratory infection, such as a cold, the flu or pneumonia. “It’s phenomenal,” he said.

Sharp knows he can’t prove it, but he attributes his rise in T cell levels to his illness-free year.

The scientists used a type of genome manipulation that employs “zinc fingers,” which are two protein strands bound by a zinc atom that resemble a finger. They precise “edit” genetic material.

For both of the studies, researchers collected T cells from the blood of each participant and with zinc fingers deleted the gene for the HIV attachment site. The patient’s own genetically modified cells were then reinfused into his blood.

In the Sangamo-run trial in California, Sharp and eight others had been taking medications that had driven HIV to an undetectable level in their blood. But they still had low T cell counts — the sign of a weakened immune system vulnerable to disease. HIV infections can lead to AIDS, the syndrome in which the weakened immune system is unable to fight off a range of serious infections.

The California study is expected to end in 2012. Sangamo BioSciences said results so far show the altered T cell infusions led to “unprecedented improvements” in all the men’s T cell counts compared with prescription drugs, including antiretroviral therapy.

The six men in the University of Pennsylvania trial also were taking HIV medications that had cleared the virus from their blood but had high T cell counts — so their immune systems were relatively strong.

They were given a 12-week “drug holiday” to test the effect of the altered cells alone.

As expected, Tebas said, their HIV blood levels spiked.

But then with infusions of their modified T cells, the HIV levels declined. One participant who carries a gene that naturally creates T cells lacking the HIV receptor even cleared the virus without help of drugs.

Tebas said the man simply had more of the modified T cells in his blood, given his natural supply and the infused T cells.

“So it clearly suggests it’s a dose issue,” Tebas said.

Sangamo BioSciences next plans to begin studying the effect of the modified T cells on those who are HIV-positive and also carry one of the genes for HIV resistance.

“It’s promising,” said Dr. Jay Levy, a University of California at San Francisco AIDS researcher who co-discovered HIV. “You can’t say anything less than that or any more than that. But the results put forward are very encouraging.”