Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis
Authors
Ding, HongliuSchwarz, Dianne S.
Keene, Alex Carl
Affar, El Bachir
Fenton, Laura
Xia, Xugang
Shi, Yang
Zamore, Phillip D.
Xu, Zuoshang
Student Authors
Alex KeeneAcademic Program
NeuroscienceUMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2003-08-26Keywords
Alleles; Amyotrophic Lateral Sclerosis; Animals; Drosophila melanogaster; Gene Expression Regulation, Enzymologic; Gene Silencing; Gene Therapy; Genes, Dominant; Genetic Vectors; Green Fluorescent Proteins; Humans; Luminescent Proteins; Mice; Point Mutation; RNA Interference; RNA Polymerase III; RNA, Small Interfering; Superoxide Dismutase; TransfectionLife Sciences
Medicine and Health Sciences
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
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.Source
Aging Cell. 2003 Aug;2(4):209-17.
DOI
10.1046/j.1474-9728.2003.00054.xPermanent Link to this Item
http://hdl.handle.net/20.500.14038/33646PubMed ID
12934714Related Resources
ae974a485f413a2113503eed53cd6c53
10.1046/j.1474-9728.2003.00054.x