microRNA Biology:

Since microRNAs have functions in multiple biological pathways, altered expression or function of microRNAs give rise to numerous diseases including cancer, fibrosis, metabolic disorders and inflammatory disorders. The demonstration that a number of microRNAs are up-regulated in a particular disease phenotype has provided the rationale to use anti-miR technology to hybridize a chemically modified oligonucleotide to the target region of the microRNA and antagonize its aberrant function, thus restoring the balance of normal gene regulation inside the cell. This anti-miR strategy therefore provides a unique approach to multiple diseases by utilizing oligonucleotides to target microRNAs that are dysfunctionally up-regulated. Developing microRNA therapeutics requires an understanding of microRNA targets as well as the pathways they regulate. Since microRNAs regulate networks of genes, understanding links between microRNA targets and function becomes a challenge in network biology. Regulus scientists are developing novel methods and algorithms to monitor the activity of microRNA-modulating drugs and to understand the functional consequences of gene network alterations.

Pharmacology:

The association of microRNA dysfunction with disease has created enormous potential for selective modulation of microRNAs using anti-miR oligonucleotides, which are rationally designed and chemically modified to enhance target affinity, stability, and tissue uptake. When aberrantly expressed or mutated, microRNAs cause significant changes in critical biological pathways and, therefore, represent potential targets whose selective modulation could alter the course of disease. From a mechanistic view, the inhibition of the microRNA target is based on the specific annealing between the microRNA and the anti-miR. A stable, high-affinity binding of the anti-miR to the microRNA will compete with the binding to the mRNA and effectively sequester the microRNA and prevent it from binding to the 3’ UTR target region. Pioneering studies by Regulus Therapeutics and others have demonstrated that modulating microRNAs through anti-miR oligonucleotides can effectively regulate biological processes and produce therapeutically beneficial results by restoring proper target gene regulation. And most recently, advances in oligonucleotide chemistry have yielded oligonucleotides modified with novel 2’,4’-constrained 2’O-ethyl (cEt) nucleotides that display improved potency and stability over previous generations. The ability to achieve increased inhibitory potency with this next generation bicyclic nucleic acid chemistry will likely make a significant positive impact on the current design of anti-miR inhibitors for a vast array of microRNA disease targets. Using microRNA therapeutics to treat human diseases requires knowledge about functional consequences of microRNA modulation via pharmacologic agents. Optimal therapeutic targets will result from skillful alignment of specific oligonucleotide drug properties with therapeutically relevant biological functions of microRNAs. Development of microRNA-modulating drugs also requires optimization of their pharmacological properties (biodistribution, pharmacokinetics, safety, etc.). Regulus scientists have vast experience in pharmacologically modulating microRNAs using oligonucleotides in animal models. Regulus is uniquely positioned for successful integration of the prerequisites necessary to develop effective microRNA therapeutics because of its streamlined synergy among all of the required technologies.