Title
Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis
Academic Program
Neuroscience
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2003-08-26
Document Type
Article
Disciplines
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
Abstract
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.
DOI of Published Version
10.1046/j.1474-9728.2003.00054.x
Source
Aging Cell. 2003 Aug;2(4):209-17.
Journal/Book/Conference Title
Aging cell
Related Resources
PubMed ID
12934714
Repository Citation
Ding H, Schwarz DS, Keene AC, Affar E, Fenton L, Xia X, Shi Y, Zamore PD, Xu Z. (2003). Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. GSBS Student Publications. https://doi.org/10.1046/j.1474-9728.2003.00054.x. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/313