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Buoyed by In Vitro Data, UCLA Researcher Says Stem Cell-Based RNAi Rx May Fight HIV

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Many academic and private-sector RNAi researchers believe that HIV is one of the most promising targets for RNAi-based therapeutic intervention. One of these is Irvin Chen, director of the UCLA AIDS Institute, who has recently begun testing a stem cell-based RNAi treatment in monkeys, and presented in vitro data at the first meeting of the Oligonucleotide Therapeutics Society last week in New York City.

However, Chen conceded that the approach faces significant hurdles, including the prerequisite to destroy a patient's existing stem cell population through radiation therapy — a risky proposition for individuals with HIV because it could sap their already-weakened immune system.

"I think that RNAi is going to be a good approach for HIV disease," Chen told RNAi News this week. "We have a very discrete target, the virus, and either directly targeting the virus itself or … knocking out a co-receptor for HIV-1 … will be a very effective means of preventing HIV replication.

"RNAi [also] can be administered through a gene-therapy approach via reconstitution of the hematopoietic system," Chen continued. "Since in advanced HIV disease the immune system is wreaked, [this gene therapy approach allows you] to create a new immune system while at the same time protecting those cells from HIV infection."


This gene therapy approach "allows you] to create a new immune system while at the same time protecting those cells from HIV infection."

According to Chen, the approach he is taking, which he said is a proof-of-concept study, involves treating a rhesus macaque with cytokines that increase levels of stem cells in the blood. "Basically, [the treatment] mobilizes stem cells from the bone marrow so that they appear in the blood," he explained. "Then, you can harvest those stem cells, purify them, put in whatever gene therapy reagent you want, say a vector expressing RNAi, and infuse those back into a patient" intravenously.

The vector Chen is using expresses an siRNA against CCR5, a co-receptor essential for replication in about 95 percent of all HIV-1 strains, he said. "Experiments [on the importance of CCR5] have already been done in nature — there are people that are naturally resistant to HIV because they lack CCR5. They can't be infected at all by those strains of HIV that use the co-receptor."

He added that HIV-infected people who are CCR5 heterozygous don't experience as rapid a progression to full-blown AIDS as individuals with normal CCR5 genotypes. "Even though they only have half as much CCR5 on their T-cells as other people, these individuals show much delayed progression to AIDS."

Chen noted that his approach faces some big hurdles, including the prerequisite ablation of a patient's stem cell population. "The patients need to be treated with drugs or radiation to suppress the existing hematopoietic cells that are in the body as much as possible," he said. "If you don't get rid of the existing hematopoietic cells, the new stem cells that you put in don't seem to take very well.

"Treatments like that are going to be tough to do for HIV patients who are already immunosuppressed to begin with," Chen added. "But at the moment at least, that's the best way to get stem cells into people [and] in the future I think we're going to see other ways without such dramatic measures."

Additionally, there is the problem of HIV's ability to mutate and become immune to treatment. However, Chen believes that "if you can reduce the population of viruses to such a low level that even if you do get mutations, it's unlikely you'll get a virus carrying that mutation within your population.


"Basically, [the treatment] mobilizes stem cells from the bone marrow so that they appear in the blood. Then, you can harvest those stem cells, purify them, put in whatever gene therapy reagent you want, say a vector expressing RNAi, and infuse those back into a patient" intravenously.

"That's the way all HIV drugs work now — there's always the chance of mutation, but if you can reduce the viral load in the body to … a low level that the chances of the mutation occurring within the remaining viruses is low," he said.

At the Oligonucleotide Therapeutics Society meeting, Chen presented in vitro data showing that his approach could be used to make human T-cells resistant to HIV infection. He also noted that about four weeks ago he and his colleagues, which include California Institute of Technology President and Nobel Laureate David Baltimore, began non-human primate experiments.

He said that he expects to see data from the monkey work in a few months "because we have to wait for their immune systems to fully restore after the [stem cell] transplant" before they can be evaluated to see if they are expressing CCR5.

"If we do see a reduction, the next step would be to challenge these animals with SIV" to see if they are resistant, he said.

— Doug Macron ([email protected])

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