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NIH Re-Issues PAs for Developing New RNAi Chemistry, Delivery Technologies

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The National Institutes of Health have re-issued two program announcements seeking research proposals from small businesses and non-profit research institutions focused on improving the chemistry and targeted delivery of RNAi molecules.

The announcements were first issued in January, but were re-issued last week in order to include information regarding new application submission guidelines, an NIH spokesman told RNAi News via e-mail this week.

According to the NIH, the PAs are designed to foster the development of "new approaches and chemical modifications that will increase the long term stability, delivery, and targeting of siRNAs in cells and tissues for laboratory and therapeutic applications.

"The discovery of RNAi has revolutionized genetic research, and is on the verge of spawning an entirely new class of drugs to treat human genetic diseases, provided that significant barriers in delivery and targeting can be overcome," the NIH said in the announcement. "The need to combine high specificity with high potency is important to the continued development of siRNA in research and therapy development."

As such, the NIH is calling for applications for research projects focused on "techniques and technologies leading to improved chemical synthesis and delivery of RNAi, particularly those incorporating chemical modifications that change the properties of the siRNA molecules to increase their stability and their ability to be delivered more efficiently to target cells without increasing their toxicity."


"The discovery of RNAi has revolutionized genetic research, and is on the verge of spawning an entirely new class of drugs to treat human genetic diseases, provided that significant barriers in delivery and targeting can be overcome."

Examples of the kinds of research proposals the NIH is accepting under these PAs include, but are not limited to, the development and identification of chemical modifications to improve thermal stability of dsRNA, such as locked nucleic acids or hexitol nucleic acids; the development of nucleic acid modifications, such as 2'-flurobases or 3'-5' phosphoramidate, leading to resistance to nuclease digestion but still allowing efficient processing by Dicer; the identification of chemical modifications leading to preferential strand uptake by RISC, that will enhance specificity and reduce off-target effects; and the development of chemical modifications, such as 2,6-diaminopurine, that enhance base-pairing interactions between the siRNA and targeted mRNA.

Additional examples include the development of chemical modifications that will allow or regulate distribution to target tissues, such as across the blood-brain-barrier; the identification of chemical modifications, such as phosphorothioate linkages, that will enhance the pharmacokinetic properties of siRNA; the development of improved instrumentation that will synthesize long oligonucleotides reliably and with high fidelity; and the development of systems for conditional expression of siRNAs.

Under the first PA, the NIH will fund projects conducted by small business concerns using the Small Business Innovation Research grant mechanism. Applications for phase I, phase II, and fast-track grants will be considered.

Under the second PA, the NIH will fund research efforts conducted by small businesses in partnership with non-profit research institutes using the Small Business Technology Transfer grant mechanism, and phase I, phase II, and fast-track applications will be considered.

The NIH said that it is accepting applications seeking up to $100,000 in total costs per year, for periods up to two years, for phase I projects. Phase II projects may request up to $500,000 in total yearly costs for periods up to three years.

"The number of awards made under this solicitation will depend on the overall scientific merit of the applications and the availability of funds," the NIH said.

NIH institutes participating in the PAs are: the National Institute of Neurological Disorders and Stroke; the National Cancer Institute; the National Center for Research Resources; the National Heart, Lung, and Blood Institute; the National Human Genome Research Institute; the National Institute on Aging; the National Institute of Allergy and Infectious Diseases; the National Institute of Biomedical Imaging and Bioengineering; the National Institute on Drug Abuse; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Dental and Craniofacial Research; the National Institute of General Medical Sciences; and the National Institute of Mental Health.

The NIH noted that the NIBIB has a specific interest in projects developing new delivery vehicles for RNAi molecules. The PAs expire on Jan. 3, 2008.

— Doug Macron ([email protected])

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