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
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.
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
DiFiglia, Marian; Sena-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.; and Aronin, Neil, "Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits" (2007). GSBS Student Publications. 381.