Therapeutic targeting of microRNAs is a dynamic environment with novel opportunities and challenges. microRNAs serve as “command and control” nodes, directly coordinating the expression of scores of functionally related genes, ultimately acting at the level of systems biology. This is fundamentally different from the single-protein single-target approach that is the foundation of most small molecule and biologic drugs. Because of the novelty of this approach, we have adopted a development strategy of “progressive program de-risking.” Central to this strategy is the transition from discovery to mechanistic proof-of-concept and ultimately to clinical proof-of-concept.
Our discovery strategy focuses on identification of microRNAs that have the potential to reprogram the key cells involved in disease pathogenesis. When available, we use human-derived model systems, including induced pluripotent stem cells (iPS) to validate the target, screen multiple product candidates and identify a molecular signature of direct target repression and secondary changes in systems biology. That molecular signature provides candidates for pharmacodynamic (PD) biomarkers essential for success in the early phase of human clinical trials.
Initial steps in the clinic are designed to build confidence in the safety and tolerability of a product candidate while simultaneously testing the ability of antimiR or promiR oligonucleotides to engage and affect the target or targets. We try to separate the evaluation of target engagement from drug delivery. For instance, in our fibrosis program, we are testing the effects of promiR-29 on cutaneous fibrosis prior to testing effects on eye, lung and other organ fibrosis. By first validating the pairing of the drug with its targets, we plan to deliver mechanistic proof-of-concept, establish the exposure-response relationship and optimize PD biomarkers. This information is designed to lower the risks of the program and provide the tools necessary to either progress directly to clinical proof-of-concept or to optimize the delivery strategy for more challenging organs such as the heart and lung.