Development of miRNA-modulating drug for neurologic diseases

Development of miRNA-modulating drug for neurologic diseases

MicroRNAs (miRNAs) modify protein expression by specifically interfering with the transcription of targeted genes and participate in the pathogenesis of various diseases. Here we present recent progresses about the drug development targeting miRNAs involved in neurologic diseases. In Alzheimer’ disease (AD), cognitive deterioration is associated with progressive synaptic dysfunction. Because AD brains are deficient in brain-derived neurotrophic factor (BDNF) that regulates synaptic plasticity and memory, experimental strategies have aimed at increasing BDNF levels. We showed that miR-206 regulates BDNF and memory function in AD, and developed miR-206-based therapeutics in AD. The brains of Tg2576 AD transgenic mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and a miR-206- eutralizingantagomir (AM206) prevented the detrimental effects of amyloid-β42 (Aβ42) on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. To solve the issues of oligonucleodie delivery to the brain, we tried intranasal delivery. Intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice. Biodistribution and half-life of intranasally-delivered AM206 were excellent in brain and cerebrospinal fluids. We then confirmed the upregulation of miR-206 in a larger cohort of human brains. By using a high thoughput assay, we underwent lead optimization to enhance the potency and reduce the number of nucleotides. We selected three optimize leads that are hundreds times more potent than the original lead. Thus we developed miRNA-based therapeutic candidates targeting AD and optimized the lead. In epilepsy, synaptic receptors, such as glycine receptors, are dysfunctional, and agents that selectively target them may be effect for the treatment of epilepsy. We examined the ability of miRNA to regulate glycine receptor-β (GLRB) expression in the brains of mice with chronic epilepsy, and intranasal delivery of antagomir was effective for managing chronic epilepsy. In this presentation, we provide the proof-of-concept and preclinical development of the non-invasive intranasal delivery of antagomir to treat neurologic diseases.