Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits
Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Endocrinology and Metabolism
Medical Subject Headings
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 Interfering
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
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.
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Citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9. Epub 2007 Oct 16. Link to article on publisher's site