Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice.
Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutant huntingtin (htt) protein, and there are currently no effective treatments. Recently, we and others demonstrated that silencing mutant htt via RNA interference (RNAi) provides therapeutic benefit in HD mice. We have since found that silencing wild-type htt in adult mouse striatum is tolerated for at least 4 months. However, given the role of htt in various cellular processes, it remains unknown whether nonallele-specific silencing of both wild-type and mutant htt is a viable therapeutic strategy for HD. Here, we tested whether cosilencing wild-type and mutant htt provides therapeutic benefit and is tolerable in HD mice. After treatment, HD mice showed significant reductions in wild-type and mutant htt, and demonstrated improved motor coordination and survival. We performed transcriptional profiling to evaluate the effects of reducing wild-type htt in adult mouse striatum. We identified gene expression changes that are concordant with previously described roles for htt in various cellular processes. Also, several abnormally expressed transcripts associated with early-stage HD were differentially expressed in our studies, but intriguingly, those involved in neuronal function changed in opposing directions. Together, these encouraging and surprising findings support further testing of nonallele-specific RNAi therapeutics for HD.
Boudreau
Ryan L
RL
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52240, USA.
McBride
Jodi L
JL
Martins
Inês
I
Shen
Shihao
S
Xing
Yi
Y
Carter
Barrie J
BJ
Davidson
Beverly L
BL
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering