Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits
Authors
DiFiglia, MarianSena-Esteves, Miguel
Chase, Kathryn O.
Sapp, Ellen
Pfister, Edith L.
Sass, Meghan B.
Yoder, Jennifer
Reeves, P.
Pandey, Rajendra K.
Rajeev, Kallanthottathil G.
Manoharan, Muthiah
Sah, Dinah W. Y.
Zamore, Phillip D.
Aronin, Neil
Student Authors
Edith PfisterUMass Chan Affiliations
Department of Medicine, Division of Endocrinology and MetabolismDepartment of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2007-10-18Keywords
Animals; Behavior, Animal; Cerebral Cortex; Cholesterol; Dependovirus; Disease Models, Animal; *Gene Silencing; *Gene Therapy; Humans; Huntington Disease; Injections; Intranuclear Inclusion Bodies; Mice; Motor Neuron Disease; Mutant Proteins; Neostriatum; Nerve Tissue Proteins; Neurons; Neuropil Threads; Nuclear Proteins; RNA, Small InterferingLife Sciences
Medicine and Health Sciences
Neuroscience and Neurobiology
Metadata
Show full item recordAbstract
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.Source
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9. Epub 2007 Oct 16. Link to article on publisher's siteDOI
10.1073/pnas.0708285104Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33719PubMed ID
17940007Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1073/pnas.0708285104