The National Institutes of Health last month said that roughly $2.5 million has been earmarked to fund projects using oligonucleotide-based methods of gene modification, chiefly RNAi, to research the prevention and treatment of oral and craniofacial disorders.
“The primary objective of [the two-year funding opportunity] is to enhance translational research … by harnessing oligonucleotide-based approaches such as RNA interference to modify the expression of genes associated with oral, dental, and craniofacial diseases and disorders,” the NIH said.
“These diseases are complex conditions involving multiple genes and gene-environmental interactions,” the agency added. “The ability to selectively silence or modify gene expression is fundamental to understanding complex disease processes and to developing possible therapeutics and prevention strategies.”
In recent years, oligo-based methods for modifying gene expression have become widely available “based on the ease of designing and testing oligonucleotides for any host gene or pathogen whose nucleic acid sequence is known,” the NIH said.
While there are a number of technologies available for modifying gene expression in vivo, including splice- and translation-blocking morpholinos, aptamers, and chromosome-targeted small duplex RNAs that can both trigger and repress gene expression, RNAi is thus far the most developed in terms of therapeutic applications, the institute noted.
Opko Health’s wet age-related macular degeneration drug bevasiranib recently entered phase III testing (see RNAi News, 7/12/2007), and a number of phase I and phase II trials for other RNAi-based drugs are ongoing.
But these therapies are all directly delivered, evidence that the delivery hurdle facing the RNAi drug field is still present despite recent technological advances such as the use of cholesterol conjugation (see RNAi News, 9/20/2007).
Still, effective siRNA uptake in the respiratory tract has been shown possible, though not simple, after intranasal topical application (see RNAi News, 9/16/2007), while research into the topical delivery of siRNA to the cervix and vagina has been preliminary but promising (see RNAi News, 1/25/2007).
“These findings suggest that the oral mucosa may also present an accessible portal of entry after topical application of direct injection of siRNA,” according to the NIH.
“These diseases are complex conditions involving multiple genes and gene-environmental interactions. The ability to selectively silence or modify gene expression is fundamental to understanding complex disease processes and to developing possible therapeutics and prevention strategies.”
“Research is needed to assess if oligonucleotide-based methods can be used for the treatment of inflammatory oral diseases, mucosal malignancies such as head and neck cancers, and other oral health conditions,” it said. “Studies are also required to identify which primary cell types in mucosal tissues mediate uptake of siRNA and which cells are amenable to therapeutic interventions.
“Finally, research is needed for the optimization of specificity and stability of RNAi-mediated functional effects in oral tissues,” giving consideration to the possibility of adverse events associated with off-target effects, the NIH added.
As such, the National Institute of Dental and Craniofacial Research will award up to $275,000 to fund between five and ten research projects in 2008 and 2009 that are focused on addressing these and other related issues.
According to the NIH, topics and approaches that would be eligible to receive funding include the silencing of inflammatory mediators, matrix metalloproteinases, and osteoclastic factors that cause bone erosion in periodontal disease; the silencing of immunological and pro-apoptotic factors that lead to the development of the autoimmune disease Sjogren’s syndrome; and the inhibition of inflammatory responses associated with oral complications of cancer therapy.
Also appropriate are projects focused on the development of strategies to enhance head and neck cancer treatments; the identification and validation of drug targets for these kinds of cancers, including salivary gland tumors; and the identification of molecules and pathways involved in head and neck cancers.
Further, the examination of genes involved in pain signaling; the manipulation of molecular pathways to enhance tooth repair or regeneration; the enhancement of hard and soft tissue repair and regeneration after craniofacial surgery; and the use of RNAi to understand immune regulation of oral diseases, autoimmunity, and host susceptibility to oral diseases are relevant to the funding opportunity.
The NIH will begin accepting funding applications on Oct. 26. The earliest anticipated start date for funded projects is next September. The funding opportunity expires on Nov. 27, 2008.
Applications for funding must include a discussion of strategies to assess and minimize non-specific and off-target effects, as well as potential immune responses triggered by gene modulation, the NIH noted.