Center for Integrative Biology and Infectious Diseases
OBJECTIVE
The goal of this initiative is to encourage applications utilizing gene silencing by RNA interference (RNAi) that are focused on the treatment and prevention of oral and craniofacial diseases and disorders. Therapeutic applications of RNAi are very broad and range from acquired diseases such as viral infections, to genetic disorders, particularly where there is a gain-of-function mutation. Most research areas within the mission of NIDCR would benefit from the application of RNAi strategies, including bone disorders, oral cancer, chronic inflammatory conditions, viral infections, autoimmune disorders, and craniofacial birth defects. The accessibility of the oral cavity to RNAi delivery makes it an attractive target for gene silencing strategies. Examples of research areas that would be appropriate for this RFA include, but are not limited to, the following:
- Silencing inflammatory mediators, matrix metalloproteinases, and osteoclastic factors that cause bone erosion in periodontal diseases
- Silencing immunological and pro-apoptotic factors leading to the development of Sjogren's syndrome
- Identification and validation of drug targets for head and neck cancers
- Dissection of key molecules and pathways involved in head and neck carcinogenesis
- Validation of target genes involved in pain signaling
- Treatment of neuropathic pain and other pain conditions that are refractory to current therapeutics
- Manipulation of molecular pathways to enhance tooth repair or regeneration
BACKGROUND
The proposed initiative is intended to encourage and facilitate translational studies within the NIDCR mission that take advantage of the efficiency and cost- savings of gene silencing. Gene silencing by RNA interference (RNAi) takes advantage of an endogenous defense mechanism for protecting cells from invading viruses and transposable genetic elements. Since the description of the phenomenon in the mid 1990’s, RNAi has emerged as a powerful strategy for silencing genes and has become a widely used tool due to its great simplicity and high efficiency.
Effective in vivo delivery of small interfering RNAs (siRNAs) to mammalian cells has proved problematic. A notable exception is the easy accessibility of mucosal surfaces. Effective delivery of siRNA has been demonstrated after topical application or direct injection in the respiratory and genital tracts and in the eye. Phase I clinical studies of siRNA to treat macular degeneration of the retina and RSV in the respiratory tract have demonstrated efficient uptake of siRNA in target tissues. Similarly, cells of the lamina propria of the vagina and cervix show efficient uptake of siRNA-lipid complexes. These results suggest that mucosal surfaces provide an effective port of entry for topically applied siRNAs.
RECOMMENDATIONS FROM WORKSHOPS
The Trans-NIH RNAi Working Group, formed in July 2004, sought to encourage the development of RNAi approaches to biomedical research problems. In FY2005 the Working Group issued a trans-NIH program announcement for SBIR/STTR grants to improve the chemistry and delivery of siRNA molecules and it issued an RFA for R01s on the delivery, processing, stability, efficiency, and regulation of siRNA in specific tissues and organs. NIDCR participated in both funding announcements but was not able to attract meritorious proposals within our mission area.