By Doug Macron
The National Institutes of Health has earmarked up to $450,000 under its Small Business Innovation Research program to help develop treatments for HIV and hepatitis C infections using RNAi and microRNAs, respectively, for intravenous-drug abusers.
“Transmission between injection drug users is a major cause for HIV infection, accounting for around 25 percent of HIV new cases,” the NIH said in a call for research proposals.
While highly active antiviral treatment, or HAART, is an effective treatment for the infection and appears to lower the chance of HIV transmission, compliance with lifelong therapy is an issue among drug users, “dampening the effectiveness of chronic HAART,” it said. “In addition, the therapy cannot eradicate the latent, low-level HIV reservoirs in patents,” and when treatment is withdrawn, the infection rebounds quickly.
A shorter-term therapeutic regimen “should be the new goal of HIV treatment,” as it would allow patients to completely eliminate the infection from reservoirs in their bodies and, for intravenous drug users, alleviate the risk of its spread through shared needles, the NIH said.
One of these regimens could include the use of RNAi-based drugs.
A number of groups have already explored the possibility of lentiviral-based shRNA treatments for HIV, but all use ex vivo delivery methods that do not appear to eradicate the infection from bodily reservoirs.
So “new strategies such as in vivo delivery of … multiple highly potent [siRNAs] and naturally enveloped proteins of HIV could be developed to effectively treat more effectively HIV-infected [intravenous drug users], especially those with latent reservoirs,” the agency said.
Co-infection with HIV and HCV is also a “significant” issue among intravenous-drug abusers, and the NIH said it is also aiming to fund research into miRNA clusters that can be harnessed to simultaneously inhibit multiple steps within the HCV life cycle by “specifically targeting various segments of the HCV gene and host-cell companion proteins."
This so-called "cluster attack" on the HCV genome "may particularly benefit human subjects who are co-infected with HIV and HCV because of the more severe nature of their disease and their more limited therapeutic choices,” the NIH added. “Combinatorial therapies, based on miRNAs, delivered via lentiviral vectors, may overcome the genetic barrier of concomitant and frequent HCV mutations.”
The agency will fund two to three six-month projects under this call for proposals, with up to $150,000 in total costs each. The deadline for proposals is Nov. 7.
Projects Under Way
A number of industry and academic research groups have been looking to RNAi and miRNAs for possible solutions to the problems of HIV and HCV.
Most recently, Santaris Pharma unveiled data from a phase IIa trial of miravirsen, a miR-122-targeting treatment for HCV (see related story, this issue). According to those data, the drug is well tolerated and can trigger “continuous and prolonged” antiviral activity that extends beyond the time of active treatment in chronic HCV patients.
Regulus Therapeutics is also developing a miR-122 antagonist to treat HCV, although its program is still in preclinical development. And SomaGenics recently released preclinical data on a short shRNA-based treatment for the disease, which it hopes to move into phase I testing next year (GSN 9/29/2011).
Meanwhile, at City of Hope, investigators recently wrapped up a clinical trial of a combination treatment for HIV/AIDS in AIDS lymphoma patients. The treatment 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.
As reported by Gene Silencing News earlier this year, the research team is planning a second clinical study with an improved version of the therapy (GSN 3/17/2011).
And at the University of Amsterdam, Ben Berkhout and colleagues have been pursuing an RNAi-based cure for HIV for years. In 2009, the investigators reported on the use of extended shRNAs to combat HIV.
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