RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model.
Huntington's disease (HD) is a fatal, dominant neurogenetic disorder. HD results from polyglutamine repeat expansion (CAG codon, Q) in exon 1 of HD, conferring a toxic gain of function on the protein huntingtin (htt). Currently, no preventative treatment exists for HD. RNA interference (RNAi) has emerged as a potential therapeutic tool for treating dominant diseases by directly reducing disease gene expression. Here, we show that RNAi directed against mutant human htt reduced htt mRNA and protein expression in cell culture and in HD mouse brain. Importantly, htt gene silencing improved behavioral and neuropathological abnormalities associated with HD. Our data provide support for the further development of RNAi for HD therapy.
Harper
Scott Q
SQ
Program in Gene Therapy, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Staber
Patrick D
PD
He
Xiaohua
X
Eliason
Steven L
SL
Martins
Inês H
IH
Mao
Qinwen
Q
Yang
Linda
L
Kotin
Robert M
RM
Paulson
Henry L
HL
Davidson
Beverly L
BL
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins