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 M, Sena-Esteves M, Chase KO, Sapp E, Pfister EL, Sass MB, Yoder J, Reeves P, Pandey RK, Rajeev KG, Manoharan M, Sah DW, Zamore PD, Aronin N. (2007). Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. GSBS Student Publications. https://doi.org/10.1073/pnas.0708285104. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/381