We focused on designing siRNA therapeutics for Charcot–Marie–Tooth disease type 1A (CMT1A), caused by PMP22 gene duplication and overexpression. Candidate siRNAs were selected to minimize off-target effects, avoid immune activation, and ensure structural stability. Modeling and docking simulations evaluated binding affinity with Argonaute 2 (Ago2), integrating ΔG, HADDOCK score, buried surface area, and seed region exposure. Three top candidates (siP1, siP2, siP3) showed strong binding, favorable thermodynamics, and low off-target risk. This work presents a robust framework for rational siRNA design in CMT1A and other gene-duplication disorders.