Background and Objectives We assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease. Methods We used next-generation whole-genome miRNA sequencing to determine CSF miRNA expression in 75 patients with Parkinson disease after single random ascending doses of nilotinib and longitudinal miRNA expression after daily nilotinib, 150 and 300 mg, vs placebo for 1 year. Results Significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the blood-brain-barrier components, primarily collagen, were observed over 1 year, suggesting impairment of these pathways in Parkinson progression in these patients. Different miRNAs that indicate activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib, 300 mg vs 150 mg, or placebo group, and these changes correlated with clinical outcomes. No changes were observed in miRNAs after a single dose of nilotinib vs placebo. Discussion This study suggests vascular and autophagy defects in Parkinson progression. Nilotinib, 300 mg, reverses these effects via alteration of miRNA expression, suggesting epigenomic changes that may underlie long-term disease-modifying effects. Trial Registration Information Clinical trial registration number: NCT02954978.

Congenital melanocytic nevi (CMN) are pigmented skin lesions present at birth with a variable risk of developing into melanoma over time. The mitogen-activated protein kinase signaling (MAPK) pathway plays a critical role in the development and progression of CMN, making it a key target for therapeutic interventions. Precision medicine aims to optimize therapeutic efficacy while minimizing adverse effects by tailoring treatments to individuals’ genetic and molecular profiles. This literature review examines the potential of precision medicine in managing CMN, with a specific focus on MEK inhibition within the MAPK pathway, summarizing current preclinical and clinical evidence, mechanisms of action, and therapeutic integration with surgical management strategies. Although early results are promising, the need for personalized treatment strategies, informed by genetic testing and biomarker profiling, is emphasized to improve the management of CMN and reduce the risk of malignant transformation. Further research is necessary to establish the long-term safety and effectiveness of MEK inhibition in CMN therapy, which could offer a more targeted and individualized approach to care.