Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a 
therapeutic strategy for downregulating a single mutant allele with minimal 
suppression of the corresponding wild-type allele. This approach has been 
effectively used to target autosomal dominant mutations and single nucleotide 
polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we 
propose ASP-siRNA as a preferable choice to target duplicated disease genes, 
avoiding potentially harmful excessive downregulation. As a proof-of-concept, we 
studied autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) due 
to lamin B1 (LMNB1) duplication, a hereditary, progressive and fatal disorder 
affecting myelin in the CNS. Using a reporter system, we screened the most 
efficient ASP-siRNAs preferentially targeting one of the alleles at rs1051644 
(average minor allele frequency: 0.45) located in the 3' untranslated region of 
the gene. We identified four siRNAs with a high efficacy and allele-specificity, 
which were tested in ADLD patient-derived fibroblasts. Three of the small 
interfering RNAs were highly selective for the target allele and restored both 
LMNB1 mRNA and protein levels close to control levels. Furthermore, small 
interfering RNA treatment abrogates the ADLD-specific phenotypes in fibroblasts 
and in two disease-relevant cellular models: murine oligodendrocytes 
overexpressing human LMNB1, and neurons directly reprogrammed from patients' 
fibroblasts. In conclusion, we demonstrated that ASP-silencing by RNA 
interference is a suitable and promising therapeutic option for ADLD. Moreover, 
our results have a broad translational value extending to several pathological 
conditions linked to gene-gain in copy number variations.