Published online 16 June 2010 | Nature | doi:10.1038/news.2010.301

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Stem-cell transplant passes safety trial.

HIV (pictured) can find it hard to invade stem cells whose defences are bolstered by gene therapy. photodisc / Getty Images

A combination gene therapy that endows human stem cells with three ways to resist HIV has passed its first safety test in humans. Four patients with AIDS who were infused with these cells tolerated the treatment, and the cells produced their anti-HIV weapons for up to two years. The study is published today in Science Translational Medicine1.

Not enough cells were transplanted in the trial to cure the patients or even reduce their viral load. But researchers hope that after further clinical trials, combination gene therapy may replace or complement anti-retroviral drugs as a way to treat people living with HIV.

The trial piggybacked on a standard treatment, in which individuals with AIDS receive transplants of their own previously saved blood stem cells, in an attempt to prevent the development of lymphoma (blood cancer). In addition to normal blood stem cells, the patients were also given cells into which three types of RNA-based gene therapies were carried by a lentivirus.

Last year, a different research group reported on a later-stage trial in which an RNA enzyme targeting HIV was delivered to 38 HIV patients using their own blood stem cells. While the treatment was somewhat effective, it did not reduce viral load to a statistically significant degree — perhaps because levels of the therapeutic gene in the blood dropped considerably during the course of the 100-week trial2.

In another study published last year, however, German physicians found that an HIV patient who also had leukaemia was seemingly cured of both diseases by a stem-cell transplant3. The cells came from a donor who had a protective deletion in a gene that gave him natural resistance to HIV (see 'Stem cell transplant wipes out HIV').

In the current trial, the researchers engineered a combination of genetic resistance into stem cells, aiming to replace an immune system susceptible to HIV with one able to resist the virus's attack1.

Three-pronged attack

First, to stop HIV from penetrating the host cells, the researchers gave the cells an RNA enzyme that would cleave the message that codes for a protein called CCR5, preventing HIV from using the protein as a co-receptor to enter the cell. "We know from a lot of populations that this is a great target — it can downregulate [HIV levels] by 90%," says John Rossi, a molecular biologist at the Beckman Research Institute of the City of Hope in Duarte, California, who worked on the trial.

But interfering with CCR5 is not foolproof, because HIV can evolve other ways of penetrating the cell. "If somehow the virus should get into these cells," Rossi explains, "then we have the cells armed with two different approaches" to fight back. So the researchers used a second mode of attack, and inserted a decoy RNA that interferes with a viral protein called tat, which is important for replication. Third, they used a technique called RNA interference (RNAi), in which they deployed a short sequence of RNA to degrade the message coding for that same viral protein and one of its partners in crime. Such different mechanisms will make it harder for viral resistance to develop, Rossi notes.

In three of the four patients, the blood stem cells continued to produce these RNAs 18–24 months after they had received the transplant. The patients also showed no adverse reactions to the vector — a long-standing concern with gene therapy.

Early promise

"It's a small study, but it's a step in the right direction," says Pablo Tebas, a clinical researcher at the University of Pennsylvania in Philadelphia who works on gene therapy and vaccines for HIV. "The most promising thing is that it shows you can modify stem cells in a way that makes them [HIV-]resistant, and the progeny of those cells would still be resistant to HIV and would still be functional." Tebas's group, in collaboration with Sangamo, a biotechnology company based in Richmond, California, is conducting a trial with a therapy that aims to delete the CCR5 protein in cells.

To make sure that the therapy was safe — and that patients received enough non-engineered cells to treat their lymphoma — Rossi says that the researchers could only include a small proportion of engineered cells in the transplanted mix. That was not enough to reduce the patients' viral load. But the team did see promising hints that the number of engineered cells increased when levels of virus in the blood went up, suggesting that these cells are selected for at the crucial time.

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"That is the stage [at which] you should reach a level of transduction where you get an increase in the number of transduced cells in the face of infection," says Premlata Shankar, an HIV vaccine researcher who works with RNAi at Texas Tech University Health Science Center in El Paso. "I don't think we are there yet."

"What we really want to do now is increase the percentage of gene-modified cells in the patient," says Rossi. He and his colleagues are planning a new trial, in collaboration with Benitech, a biotech company based in Melbourne, Australia, in which they will be able to take cell samples containing a larger number of a patient's blood stem cells and transplant only engineered cells, without diluting their effects by also transplanting natural ones.