Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) marked by myelin degradation. Myelin is a lipid-rich insulating sheath essential for efficient signal transmission and neuronal health. Despite the critical role of demyelination in MS, existing treatments do not halt disease progression or promote myelin regeneration. Recent insights from our lab underscore microRNA-145 (miR-145) as a pivotal factor hindering oligodendrocyte production, with elevated levels detected in chronic lesions of secondary progressive MS post-mortem brain tissue. To unveil the potential advantages of miR-145 depletion, we employed miR-145 deficient mice in a cuprizone autoimmune encephalitis (CAE) model, a novel MS model predominantly affecting the brain. Notably, miR-145 deficient mice exhibited enhanced myelin regeneration, accompanied by shifts in pro-inflammatory microglia/macrophage density and mRNA expression levels of essential inflammatory mediators. Exploring a therapeutic avenue, we utilized an antisense oligonucleotide (ASO) targeting miR-145. Initial tests in organotypic spinal cord slice cultures post-lysolecithin-induced demyelination revealed increased neurofilament light chain and myelin basic protein fluorescence intensities with miR-145 ASO treatment, indicating improved ex vivo remyelination. In the experimental autoimmune encephalomyelitis (EAE) model, subcutaneous miR-145 ASO injections substantially reduced miR-145 levels in both lymphoid and CNS tissues, and diminished disease severity. Ongoing assessments are underway to gauge its impact on remyelination in this model. Future investigations will delve into the acute knockdown of miR-145 in CAE and EAE models, probing associated cellular and molecular mechanisms. This study establishes a foundation for innovative therapeutic approaches targeting miR-145 in MS and other demyelinating diseases.