We developed small interfering RNAs (siRNAs) that target all isoforms of MECP2 non-selectively for severe duplication cases, as well as siRNAs that selectively target the E1 isoform with minimal impact on E2 for milder cases where the risk of treatment-related Rett-like syndromes is highest. The gene discussed is MECP2; the disease is atypical Rett syndrome.