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NIH Awards Four Grants for Projects Addressing RNAi-Delivery Challenge

The US government has in past years been a key source of funding for researchers trying to tackle the challenge of safely and successfully delivering RNAi-based therapeutics, and 2008 is no exception.
Already this year, the National Institutes of Health has awarded at least four grants supporting projects addressing the challenge, including one to Minnesota-based Innovative Surface Technologies, which in March received a six-month grant worth nearly $100,000 to develop a novel, non-viral technology for target-specific delivery of siRNAs.
Also receiving NIH funding are Bioo Scientific; University of North Carolina, Chapel Hill, researcher Leaf Huang; and Boulder, Colo.-based Aktiv-Dry.
According to the Innovative Surface Technologies’ grant abstract, the company is developing a di-block co-polymer composed of a positively charged block that complexes with siRNAs, a polyethyleneoxide block designed to prevent absorption of the molecule into non-target tissues, and a phosphane group that can be used to attach a targeting ligand.
The research, which is funded by the National Institute of General Medical Sciences, “is expected to investigate the safety and efficacy of this novel siRNA delivery system in an animal model for therapeutic application,” the abstract notes. Specific aims of the effort include optimizing the synthesis of the di-block co-polymers and the conjugation of targeting ligands, as well as the development of a method for preparing siRNA/polymer nanoparticles.
Additionally, Innovative Surface Technologies will examine the cytotoxicity of the delivery system, demonstrate its ability to silence specific genes, and investigate intracellular trafficking of the molecules.
Bioo Scientific, meanwhile, won a nine-month NIGMS grant worth roughly $172,000 to continue working on its antibody-based siRNA delivery technologies.
According to the grant’s abstract, the company is developing two types of antibody-based conjugates designed to deliver siRNAs to cells over-expressing a particular cell-surface antigen.
“The first is produced by chemically crosslinking large recombinant RNA-binding proteins to antibodies,” the abstract states. “The siRNA non-covalently associates with the targeting antibody via the RNA-binding protein.”
The second type is made by directly attaching “functional, modified siRNAs to antibodies using heterobifunctional cross-linking agents containing internal cell labile structures to promote the release of the siRNA after internalization,” it adds.

“We will encapsulate multiple sets of siRNA targeting to different cellular oncogenes to show at least an additive, if not synergistic, effect in tumor killing.”

According to Bioo Scientific, its grant will enable it to try to boost the number of siRNAs that can be attached to each antibody; covalently conjugate siRNAs to antibodies using cleavable linkers to produce immunoconjugates that are stable in plasma but can release the RNAi payload inside cells; and use the conjugates to deliver siRNAs into cultured cells and into tumor cells in mouse xenografts.
This grant, which officially begins in June, builds on a National Science Foundation award that Bioo Scientific received earlier this year (see RNAi News, 3/27/2008).
At UNC Chapel Hill, Huang is aiming to further develop an anisamide-targeted nanoparticle formulation for intravenous delivery of siRNAs to human lung cancer cells in a mouse model, according to his grant’s abstract.
Previous work with the nanoparticle technology showed that it could be used to silence epidermal growth factor receptor in cancer cells, but only with modest apoptosis and tumor growth inhibition, the abstract states. “Thus, the [NIH-funded] project will develop several independent strategies to enhance the therapeutic activity” of the siRNA nanoparticles.
“We will encapsulate multiple sets of siRNA targeting to different cellular oncogenes to show at least an additive, if not synergistic, effect in tumor killing,” Huang said in the abstract. Additionally, the microRNA let-7 will be examined for its ability to suppress tumor activity in a mouse model, as will chemically modified siRNAs.
The project will also test whether the nanoparticles can be used to deliver siRNAs to melanoma cells in mice, and determine if plasmid DNA expressing anti-cancer genes can be delivered with the siRNAs as a sort of combination therapy.
Awarded by the National Cancer Institute in early March, Huang’s grant will run until February 2013, and is worth $300,211 in its first year.
Lastly, dry-powder processing firm Aktiv-Dry was issued a six-month grant by the National Institute of Child Health and Human Development to develop a dry powder inhalation system for delivering siRNA as a treatment strategy for respiratory syncytial virus.
Alnylam Pharmaceuticals is currently testing an RNAi-based RSV treatment called ALN-RSV01 in phase II studies. Currently, the drug is being evaluated in adult lung-transplant patients naturally infected with the virus. The company plans to launch another phase II trial later this year in a pediatric population, which is viewed as the key patient population for such a drug (see RNAi News, 5/15/2008).
“The proposed inhalation system will be capable of delivering a continuous stream of micronized dry powder aerosol into the respiratory tract of children,” the company said in its grant abstract. The performance of the system, called Aktiv-Neb, will be determined by emitted aerosol size distribution, consistency of emitted dose, and the reproducibility at physiologically relevant breathing patterns for children and infants.”
After initial testing, the Aktiv-Neb system will then be tested with siRNA microparticle powders and formulations, the company said.
Financial information for this grant, which runs from June until the end of November, was not available.

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