TargetMDD: Validating microRNA-186-5p as a molecular target for early intervention in Major Depressive Disorder

This project aims to validate a novel therapeutic strategy for Major Depressive Disorder (MDD) by targeting miR-186-5p, a microRNA elevated by chronic stress and linked to synaptic dysfunction in the prefrontal cortex. Targeting this upstream, stress-responsive microRNA offers a distinct approach compared to conventional treatments focusing on downstream neurotransmitters. Our approach combines chronic stress animal models and human iPSC-derived neurons with data from post-mortem brain, serum, and cerebrospinal fluid of MDD and other stress-related psychiatric patients. We will assess if miR-186-5p inhibition reverses neuronal and behavioural changes caused by stress, establishing its therapeutic potential. In vivo validation will utilize i) light-activatable nanoparticles to deliver inhibitors with precise temporal control and ii) small extracellular vesicles loaded with the miR-186-5p inhibitor, with translational value. By correlating peripheral miR-186-5p levels with patient clinical data, we further aim to establish its potential as a patient stratification biomarker. This strategy holds promise for early intervention by potentially halting disease progression before symptoms become severe, but also for refractory MDD cases, where synaptic disruption is critical. The inclusion of animal models and patient samples from both male and female subjects addresses the significant sex bias in MDD prevalence, enhancing potential impact on all patients.