Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Academic Article uri icon


  • RNA interference (RNAi) can achieve sequence-selective inactivation of gene expression in a wide variety of eukaryotes by introducing double-stranded RNA corresponding to the target gene. Here we explore the potential of RNAi as a therapy for amyotrophic lateral sclerosis (ALS) caused by mutations in the Cu, Zn superoxide dismutase (SOD1) gene. Although the mutant SOD1 is toxic, the wild-type SOD1 performs important functions. Therefore, the ideal therapeutic strategy should be to selectively inhibit the mutant, but not the wild-type SOD1 expression. Because most SOD1 mutations are single nucleotide changes, to selectively silence the mutant requires single-nucleotide specificity. By coupling rational design of small interfering RNAs (siRNAs) with their validation in RNAi reactions in vitro and in vivo, we have identified siRNA sequences with this specificity. A similarly designed sequence, when expressed as small hairpin RNA (shRNA) under the control of an RNA polymerase III (pol III) promoter, retains the single-nucleotide specificity. Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutations.

published proceedings

  • Aging Cell

altmetric score

  • 12

author list (cited authors)

  • Ding, H., Schwarz, D. S., Keene, A., Affar, E. B., Fenton, L., Xia, X., ... Xu, Z.

citation count

  • 147

complete list of authors

  • Ding, Hongliu||Schwarz, Dianne S||Keene, Alex||Affar, El Bachir||Fenton, Laura||Xia, Xugang||Shi, Yang||Zamore, Phillip D||Xu, Zuoshang

publication date

  • August 2003