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NIH Awards Four RNAi-Related Grants in August

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Although August is traditionally a slow month for business, the National Institutes of Health has been busy, awarding four grants worth nearly $850,000 to four researchers, two from academia and two from industry, to fund their RNAi research efforts through fiscal 2005.

The first grant was awarded to Scott Hammond from the University of North Carolina, Chapel Hill, for a project focused on uncovering a link between RNAi and fragile X mental retardation. It was provided by the National Institute of General Medical Sciences and is worth $282,786 for the first year of its five-year term.

According to that grant's abstract, fragile X syndrome results from loss of expression of the Fmr1 gene, whose protein product, FMRP, is an RNA binding protein that has been shown to interact with a limited subset of neuronal mRNAs. "It is believed that translational regulation of these genes is the primary function of FMRP," the abstract notes.

Hammond stated in the abstract that he recently reported the presence of the Drosophila fragile X homolog, dFxr, as a component of the RNAi machinery. Based on this, he hypothesizes that "FMRP functions as part of the RNAi machinery, and dysfunction of this shared biological machinery is responsible for fragile X mental retardation."

With support from the NIGMS grant, Hammond will test this hypothesis by defining the composition of this shared FMRP/RNAi machinery in mammalian cells using fractionation methods and assays, the abstract states. He then intends to identify mRNA targets that are regulated by this activity and investigate the mechanism of gene regulation by the FMRP/RNAi machinery.

The second grant, worth $276,500 this year, was awarded by the National Cancer Institute to Baylor College of Medicine researcher Kaiyi Li for a project investigating an RNAi-based therapy for liver cancer.

According to this grant's abstract, the goal of the research is to examine the therapeutic potential of an siRNA targeting cyclin E, an oncogene expressed in 70 percent of liver cancers.

"Our lab recently discovered that cyclin E … [plays] a substantial role in proliferation and cell survival and could serve as a promising therapeutic target for [liver cancer]," Li stated in the abstract. "We also found that overexpressed cyc E could be suppressed up to 90 percent by siRNA targeting the coding region of cyc E [and that] depletion of cyc E in [liver cancer] induced significant inhibition of cell growth both in cultured cells and in nude mice."

The four-year grant project has four specific aims, the abstract noted: to determine the therapeutic effects of cyc E siRNA using both subcutaneous and orthotopic [liver cancer] models in mice; to examine the effect of cyc E siRNA on [liver cancer] cells versus normal hepatocytes or tissues in in vitro and in vivo models; to evaluate the therapeutic efficacy of cyc E siRNA in combination with chemodrugs; and to assess the in vitro and in vivo antitumor effect of cyc E siRNA from a tumor specific expression vector.

"We have generated a plasmid which expresses cyc E siRNA via a liver tumor specific promoter," Li stated. "The efficacy and specificity of this vector will be systematically assessed using both [cancer] cell lines and HCC xenograft models in mice."

The third grant was awarded to Zairen Sun, from Origene, by the NIGMS and is worth $164,395 for this year. It supports an effort to generate a kinase siRNA library using Dicer in order to "mimic the natural way that RNAi machinery targets and destroys specific cellular and viral RNAs," the abstract states.

The first phase of the two-year grant project involves optimizing experiments to synthesize siRNA using Dicer, and compare simultaneously the gene-silencing effects with multiple siRNAs and shRNAs constructs designed for 24 specific kinase genes, the abstract notes. The second phase "will focus on the production of siRNAs for the complete kinase gene family and real-time PCR validation of gene-silencing by co-transfection of full-length kinase clones and corresponding Dicer siRNAs."

The last grant was awarded by the NIGMS to Intradigm researcher Frank Xie to support the development of histidine/lysine (HK) polymers as transfection reagents for siRNAs. It is a six-month grant worth $124,820.

According to the grant's abstract, the goal of the project is "to evaluate the feasibility of using PT88, a member of the HK polymer family, as siRNA transfection reagent."

According to Xie, "currently available polymer-based transfection reagents are highly toxic to the cells, and [this] toxicity to the host cells may well shadow the effect of siRNA-mediated gene silencing. Therefore, a high efficient, low toxic siRNA transfection reagent is highly desired and its commercialization will significantly advance the application of siRNA in the field of gene function study and development of new therapeutics."

Xie stated that Intradigm has developed a group of HK polymers and used them as nucleic acid carriers for in vitro and in vivo delivery of siRNAs. "The in vitro transfection efficiency of plasmid DNA mediated by the HK polymers is comparable to that of polymer-based transfection reagent, while the HK polymers give a much higher in vivo transfection efficiency than both polymer-based and liposome-based transfection reagents," he noted in the grant abstract. "More importantly, the HK polymers present strong serum tolerances and exhibit minimum, if any, cytotoxicity to the transfected cells."

Specifically, Xie said he plans to "evaluate the efficiencies of PT88 mediated siRNA transfection and siRNA/DNA co-transfection in 10 cell lines that include cell lines believed easy to be transfected and cell lines believed difficult to be transfected; perform [a] comprehensive cytotoxicity study and serum tolerances study of PT88 in the cultured cells; and investigate the feasibility of PT88 for high-throughput siRNA transfection that include multiple transfection and co-transfection of plasmid DNA and siRNA duplexes."

— Doug Macron ([email protected])

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