Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits.
Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the huntingtin (Htt) gene. HD is autosomal dominant and, in theory, amenable to therapeutic RNA silencing. We introduced cholesterol-conjugated small interfering RNA duplexes (cc-siRNA) targeting human Htt mRNA (siRNA-Htt) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 CAG) Htt cDNA encoding huntingtin (Htt) 1-400. Adeno-associated virus delivery to striatum and overlying cortex of the mutant Htt gene, but not the wild type, produced neuropathology and motor deficits. Treatment with cc-siRNA-Htt in mice with mutant Htt prolonged survival of striatal neurons, reduced neuropil aggregates, diminished inclusion size, and lowered the frequency of clasping and footslips on balance beam. cc-siRNA-Htt was designed to target human wild-type and mutant Htt and decreased levels of both in the striatum. Our findings indicate that a single administration into the adult striatum of an siRNA targeting Htt can silence mutant Htt, attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD.
DiFiglia
M
M
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114, USA.
Sena-Esteves
M
M
Chase
K
K
Sapp
E
E
Pfister
E
E
Sass
M
M
Yoder
J
J
Reeves
P
P
Pandey
R K
RK
Rajeev
K G
KG
Manoharan
M
M
Sah
D W Y
DW
Zamore
P D
PD
Aronin
N
N
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D000229:Dependovirus; D004195:Disease Models, Animal; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology / Q000628:therapy; D007267:Injections; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D016472:Motor Neuron Disease / Q000473:pathology; D050505:Mutant Proteins / Q000037:antagonists & inhibitors*; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D019600:Neuropil Threads / Q000187:drug effects / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D002784:Cholesterol