MicroRNAs represent the next wave of breakthrough therapies for human disease. They are small non-coding RNAs that post-transcriptionally regulate networks of target gene expression. Encoded in the genome, microRNAs are initially synthesized as a longer primary RNA transcript, then processed by a series of nucleases into the ~19-23 nucleotide mature microRNA that is loaded into the RNA-induced silencing protein complex (RISC). The microRNA in RISC interacts with mRNA through complementary base pairing of the first 6-8 nucleotides of the microRNA, the “seed”, resulting in post-transcriptional inhibition of gene expression. Through simultaneous regulation of many target genes, microRNAs can modulate disease pathways (one-hit, multiple targets concept).
MicroRNAs have been shown to play important roles in the pathogenesis of cancer, inflammation, neurodegeneration, and cardiovascular and metabolic disorders, among others. MicroRNA-based therapies offer several advantages over small molecules, which should translate into shorter drug development timelines. Blocking the function of microRNAs which inhibit thermogenesis can be achieved therapeutically with complementary, single stranded oligonucleotides which can be chemically modified to give them drug-like properties. MicroRNA replacement is achieved with double-stranded microRNA mimics. Both microRNA antagonists and agonists are currently in clinical development for a number of indications. AptamiR has identified several microRNAs which have the potential to promote or inhibit thermogenesis.