Development of modified microRNA therapeutics

DESCRIPTION (provided by applicant): Experimental evidence accumulated in the past few years indicates that several miRNAs likely function as tumor suppressors and that the altered expression of these miRNAs likely contributes to a significant number of human cancers. Mirna Therapeutics has identified approximately ten tumor suppressor miRNAs and is in the process of developing mimetics for two of these that will be subjected to efficacy and safety studies using advanced rodent and primate studies. These studies will ultimately be used to support an IND submission to the FDA for one or more miRNA-based therapies for the treatment of cancer patients. The focus of our proposed Phase I research is to use nucleotide analogs to improve the stabilities and activities of mimetics of two miRNAs that have proven to have therapeutic activities in mouse models of several different cancers. The goal for Phase I of the project is to create mimetics that are as much as ten-fold more effective than our current unmodified mimetics in inhibiting tumor growth in mice. Modified mimetics developed during Phase I will support our Phase II effort wherein the mimetics will be coupled with delivery agents developed in a parallel program. The mimetic/delivery combinations will be evaluated for therapeutic activities and pharmacokinetics using mouse models. The Specific Aims for our Phase I research are: (1) Develop modified mimetics with favorable stabilities and equivalent activities to unmodified mimetics and (2) Verify that the modified mimetics have therapeutic activities and target specificities that are equivalent to the unmodified miRNA mimetics that we have used for our efficacy studies to date. PUBLIC HEALTH RELEVANCE: Statement of Clinical Relevance Targeted therapies have the potential to revolutionize the treatment of cancer patients. A number of naturally occurring microRNAs, a newly discovered class of genetically-encoded RNA molecules, appear to function as powerful tumor suppressors in humans. We are developing synthetic versions of two of the more powerful tumor suppressor miRNAs to create therapies that can be used to inhibit the progression of cancer.