The National Institutes of Health last month earmarked nearly $730,000 to support four companies developing in vivo RNAi delivery technologies, including three related to human drug development and one for use in animal cancer models.
The first award, a six-month grant worth $181,482, was issued by the National Institute of Allergy and Infectious Diseases to support efforts by Transgenex Nanobiotech to develop siRNA-containing nanoparticles for the prevention of HIV-1 transmission.
“The combination of siRNA and chitosan nanoparticle technology led to the development [of] nanocomplex antivirals capable of inhibiting respiratory syncytial virus infections,” principal investigator Weidong Xu wrote in the grant’s abstract, citing research by University of South Florida investigators published in 2005.
Based on these and other data, Xu hypothesizes that “multifunctional chitosan nanoparticles can effectively deliver [siRNAs] without any significant adverse effects and provide significant protection against viral infections, specifically HIV,” according to the abstract.
With the NIH funding, he and his colleagues will examine the ability of siRNA-containing chitosan nanoparticles to inhibit HIV replication in either human or monkey peripheral blood mononuclear leukocytes, with the goal of ultimately advancing the RNAi agent into non-human primate studies.
Xu’s grant runs from Sept. 1 to Feb. 29, 2009.
The second grant was awarded to an Armagen Technologies official to further develop the company’s intravenous siRNA delivery technology.
Last year, Ruben Boado, an Armagen vice president, and colleagues published a paper describing how they were able to deliver siRNAs across the blood-brain barrier of rats by using a technology that incorporates an engineered fusion protein of avidin and a cell membrane receptor-specific monoclonal antibody, which binds mono-biotinylated siRNA with high affinity. The technology is also described in US patent No. 6,287,792, which was issued to Boado and Armagen co-founder William Pardridge.
With the help of a two-year grant from the National Institute of Neurological Disorders and Stroke, which is worth about $190,000 in its first year, Boado, who is also a researcher at the University of California, Los Angeles, and colleagues aim to “engineer, express, and validate a new fusion protein comprised of avidin and a mouse/rat chimeric [monoclonal antibody] to the mouse transferrin receptor,” according to the grant’s abstract.
“A remaining … barrier to using this extremely valuable information for development of targeted therapeutics is to characterize the functional role of tumor-associated proteins.”
This antibody acts as a “molecular Trojan horse” that is expected to carry an siRNA payload across the cell membranes expressing the transferrin receptor, the abstract adds. Since this receptor is highly expressed on the blood-brain barrier, the researchers expect the technology will enable delivery to the brain, as well as other organs.
Boado’s grant runs from Sept. 15 to Aug. 31, 2010.
The National Cancer Institute issued the third grant to a pair of Optimum Therapeutics researchers who are studying whether therapeutic siRNAs can be delivered efficiently into the peritoneal cavity as a means to treat cancer.
Earlier this year, Ze Lu and Jie Wang, and colleagues from Ohio State University, described how they developed paclitaxel-loaded microparticles that can be injected directly into the peritoneum to treat ovarian cancer.
“Our laboratory has established high tumor cell density as a key barrier to intra-tumoral transport, and has since developed the tumor-priming technology to promote particulate delivery and interstitial transport in solid tumors,” the investigators wrote in their grant’s abstract. “This technology uses paclitaxel to induce apoptosis, expand the interstitial space, and consequently promote greater penetration and more even dispersal of particulates in tumor matrix.”
With the support of the NCI, the researchers aim to apply this approach to RNAi.
“We will first determine the feasibility of using [tumor-priming microparticles] as a tumor-selective delivery platform to promote delivery and penetration of liposomal siRNA into tumors,” they stated. “The experiment results will identify the optimal formulation of cationic liposomal [siRNAs] and define the conditions for using [intraperitoneal tumor-priming microparticles] to promote siRNA penetration and dispersion in … tumors.”
Following this work, the team will examine whether their technologies can boost the therapeutic abilities of survivin-targeted siRNAs in treating intraperitoneal tumors.
This grant runs from Sept. 17 to Aug. 31, 2010, and is worth $122,613 in its first year.
The NCI also awarded a two-year grant, worth $235,440 in its first year, to an Aparna Biosciences official working to adapt the company’s nanoparticle technology for use in delivering siRNAs to animal models of non-small cell lung cancer. Martin Woodle, founder of Aparna, was co-founder and former CSO of Intradigm. He left the company around the time of a corporate reorganization (see RNAi News, 11/22/2006).
New laser micro-dissection and protein extraction and analysis technologies applied to tissue samples have improved researchers’ understanding of cancer biochemistry and pathology, however, “a remaining … barrier to using this extremely valuable information for development of targeted therapeutics is to characterize the functional role of tumor-associated proteins,” Woodle wrote in the grant’s abstract.
RNAi holds promise for addressing this issue, but has been “confined largely to cell culture studies, with limited methods for in vivo administration in animal disease models … and none available as a research reagent,” he noted. “Our hypothesis is that we can adapt our cationic polypeptide nucleic acid nanoparticle technology, which we have found effective for in vivo delivery of RNAi agents to a primary breast cancer xenograft model, for a set of metastatic and primary [non-small cell lung cancer] xenograft tumor models.”
Specifically, the project aims to establish the xenograft models, adapt and optimize the nanoparticle structure for in vivo delivery of a positive control RNAi agent, and evaluate the efficacy of the nanoparticle for target validation using a set of candidate targets found to be differentially expressed in either metastatic or primary tumor lesions.
If the effort is successful, the company then aims to begin commercially developing an in vivo RNAi reagent for validating non-small cell lung cancer gene function.
Woodle’s grant is set to run from Sept. 16 until Aug. 31, 2010.