Benitec said last week that it has signed a sponsored research agreement with the City of Hope to develop an HIV/AIDS treatment using the company’s DNA-directed RNAi technology, which will be evaluated in patients with AIDS lymphoma.
The clinical trial, which is expected to enroll five patients, would be an extension of the work of John Rossi, professor and chair of molecular biology at the City of Hope’s Beckman Research Institute. According to Rossi, the therapy involves the mobilization of stems cells in patients using granulocyte colony stimulating factor. Once the stem cells begin circulating peripherally, they can be collected, isolated, and genetically modified with a lentiviral vector containing therapeutic genes, he told RNAi News.
The patients undergo full chemoablation, which kills both the regenerative cells of the bone marrow and lymphoma cells, and then the stems cells are infused back into their bloodstreams so that they can migrate to, and engraft in, the marrow.
Under the Benitec-funded project, the stem cells will be transduced with vectors containing three 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.
“By inserting the ddRNAi constructs into their stem cells, [patients] will be producing anti-HIV shRNAs, and presumably these will develop into T-cells, macrophages, monocytes — all the cells that the stem cells mature into — and they will be resistant to HIV,” Rossi said. But the therapy, he noted, “is a triple-inhibitory scheme. The shRNA [is] the most potent of the three, but the other two are ancillary and work synergistically.”
Rossi said that this autologous stem cell transplant procedure — minus the gene therapy components — has been used to treat 17 AIDS lymphoma patients at the City of Hope, while five others have received the transplanted stem cells with just the ribozymes. Now, by including ddRNAi in the therapy, Rossi said he hopes to come up with a permanent treatment for HIV/AIDS in a patient population that is already known to benefit from the stem cell transplant in a full bone marrow transplant setting.
“It’s a trial that you might not do in a non-lymphoma patient because it requires bone marrow transplantation, which is a pretty serious business,” Rossi said. “But the fact that they benefit tremendously from the bone marrow transplant for the lymphoma, and you can introduce antiviral genes at the same time, makes this a really attractive population. It’s a win-win situation as far as I can tell.”
The filing of an investigational new drug application to begin testing of the therapy in humans is expected to occur before the end of the year, with the actual commencement of the clinical study in mid- to late 2005, Rossi said. He noted that a pre-IND meeting, while not necessary, is planned. Sara Cunningham, COO of Benitec, said that the company has already sent out a letter requesting the meeting with the US Food and Drug Administration.
The production of the vectors is expected to be handled through the National Gene Vector Laboratories, according to Rossi. “What we’re producing right now [under cGMP conditions at the City of Hope] is the plasmid that contains the therapeutic genes,” he noted. “We’ll produce all of the packaging vectors that go along with that, and they’ll all be shipped to [Ken] Cornetta [at the Indiana University Vector Production Facility] who will then do the packaging and produce the vector under GMP conditions there.”
Although he is optimistic about the prospects of the procedure, Rossi said that it is largely a proof-of-concept effort for the ddRNAi technology and that he doesn’t expect the phase I version of the therapy to translate directly into a final HIV/AIDS treatment.
“[Benitec] is interested in getting the experimental results from this [research],” he said. “To me, it doesn’t seem like these will be the genes that you will ultimately use in a commercial venue. If Benitec wanted to develop a commercial [product], they’d probably have multiple … shRNA constructs” in order to deal with HIV mutations.
Cunningham agreed, and told RNAi News that “it’s very easy for RNA viruses to get around small molecule drugs — that’s why you have [highly active anti-retroviral therapy]. What we’re hoping to do is step … back a level, so that you’re not looking at the protein level, you’re looking at RNA,” she said.
“As far as what we see as a drug, we would expect it to be a multi-target because of the nature of the virus we’re going after,” Cunningham noted, adding that a phase II trial of a ddRNAi-based HIV/AIDS treatment would likely be done in virus-infected patients who had not yet advanced to the lymphoma stage.
Although Benitec fully expects to conduct the clinical trial with Rossi and the City of Hope, an agreement formalizing the collaboration has yet to be signed.