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City of Hope Preps for Second Study with Expressed RNAi AIDS Treatment


By Doug Macron

Roughly three years after dosing the first patient in a small trial testing an expressed RNAi-based HIV/AIDS therapy in lymphoma patients carrying the virus, the City of Hope is planning to initiate a second study that will examine an improved version of the treatment, Gene Silencing News has learned.

In the first study, four AIDS lymphoma patients received treatment and are doing well, John Rossi, one of the trial's investigators, said. While the scope of the trial, as well as the requirement that patients remain on anti-retroviral drugs, preclude any determination of efficacy, the treatment does appear safe.

“The next step is to optimize it so it is more robust,” at which point it may be appropriate to take the patients off their AIDS medicines to see if the RNAi approach can protect cells from the virus, he said. The new trial could begin as early as this year.

The treatment under development involves mobilization of stem cells in patients using granulocyte colony stimulating factor. Once the stem cells begin circulating peripherally, they are collected, isolated, and genetically modified with a lentiviral vector containing three therapeutic genes: DNA that encodes for shRNAs targeting the tat-rev exon, a ribozyme that cleaves the mRNA for CCR5, and a nucleolar-localizing TAR decoy.

The patients undergo full chemoablation, killing the regenerative cells of the bone marrow and lymphoma cells. Then, the modified stem cells are infused back into their bloodstreams so that they can migrate to, and engraft in, the marrow. The idea is that the stem cells will carry the anti-HIV shRNAs and, when they mature into other cells such as macrophages and monocytes, these will be resistant to the virus. The ribozyme and TAR decoy components of the treatment are designed to enhance the inhibitory effect of the shRNA.

City of Hope has been testing the treatment on AIDS patients who have developed lymphoma because the stem cell transplant component might not be appropriate for people only infected with the virus but is an accepted treatment for the cancer.

In the years since the trial participants were treated, “we've seen marking in three of the four patients long term, showing the genes had been introduced into pluripotent stem cells,” Rossi said. “One of the patients has very low transduction efficiency — we just didn't see much beyond the first couple of months.”

Although the study was not powered for efficacy, the investigators did observe “little bursts of the gene-marked cells in a couple of patients when they went off their anti-retrovirals for various reasons, suggesting that the cells that had the protection were surviving,” Rossi explained, although he cautioned that the effect was transient and not statistically significant.

Most encouraging is the “long-term marking of cells [with the vector sequences] that are derived from hematopoietic progenitor cells,” he said. “This is really a big breakthrough from our point of view.”

In light of these findings, Rossi and his colleagues are planning the second trial, which will use a slightly modified protocol. The vector and patient population will be the same, but the researchers will take a “different approach to introducing the vector into their stem cells to try to optimize the number of cells that have the therapeutic genes.”

More specifically, the new protocol involves an alternative method of collecting and modifying the patients' stem cells, which is expected to “increase the number of genetically modified cells in the patients,” he said.

“Right now it's low — it's less than one percent — and we don't think that's enough to create any kind of treatment strategy,” Rossi noted. “But if we can show that we can take the same population of patients and modify their cells in a slightly different fashion to give enhanced transduction and engraftment of the gene-marked cells, we have a much better chance of seeing high levels of marking.”

If the level of peripheral blood marked cells can be increased to more than five or ten percent, “we can start asking the efficacy question, 'Can we safely take them off their anti-retroviral drugs for an extended period to see if they are still protected from viral infection?'” he said.

Have topics you'd like to see covered in Gene Silencing News? Contact the editor
at dmacron [at] genomeweb [.] com.

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