{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:44:42Z","timestamp":1791333882255,"version":"4.3.1"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"43","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,10,23]]},"abstract":"<jats:p>\n                    Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat in the\n                    <jats:italic>huntingtin<\/jats:italic>\n                    (\n                    <jats:italic>Htt<\/jats:italic>\n                    ) 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\n                    <jats:italic>Htt<\/jats:italic>\n                    mRNA (siRNA-\n                    <jats:italic>Htt<\/jats:italic>\n                    ) into mouse striata that also received adeno-associated virus containing either expanded (100 CAG) or wild-type (18 CAG)\n                    <jats:italic>Htt<\/jats:italic>\n                    cDNA encoding huntingtin (Htt) 1\u2013400. Adeno-associated virus delivery to striatum and overlying cortex of the mutant\n                    <jats:italic>Htt<\/jats:italic>\n                    gene, but not the wild type, produced neuropathology and motor deficits. Treatment with cc-siRNA-\n                    <jats:italic>Htt<\/jats:italic>\n                    in mice with mutant\n                    <jats:italic>Htt<\/jats:italic>\n                    prolonged survival of striatal neurons, reduced neuropil aggregates, diminished inclusion size, and lowered the frequency of clasping and footslips on balance beam. cc-siRNA-\n                    <jats:italic>Htt<\/jats:italic>\n                    was designed to target human wild-type and mutant\n                    <jats:italic>Htt<\/jats:italic>\n                    and decreased levels of both in the striatum. Our findings indicate that a single administration into the adult striatum of an siRNA targeting\n                    <jats:italic>Htt<\/jats:italic>\n                    can silence mutant\n                    <jats:italic>Htt<\/jats:italic>\n                    , attenuate neuronal pathology, and delay the abnormal behavioral phenotype observed in a rapid-onset, viral transgenic mouse model of HD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0708285104","type":"journal-article","created":{"date-parts":[[2007,10,16]],"date-time":"2007-10-16T23:29:01Z","timestamp":1192577341000},"page":"17204-17209","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":367,"title":["Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits"],"prefix":"10.1073","volume":"104","author":[{"given":"M.","family":"DiFiglia","sequence":"first","affiliation":[{"name":"*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Sena-Esteves","sequence":"additional","affiliation":[{"name":"*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Chase","sequence":"additional","affiliation":[{"name":"Departments of \u2020Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Sapp","sequence":"additional","affiliation":[{"name":"*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Pfister","sequence":"additional","affiliation":[{"name":"Departments of \u2020Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Sass","sequence":"additional","affiliation":[{"name":"Departments of \u2020Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Yoder","sequence":"additional","affiliation":[{"name":"*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Reeves","sequence":"additional","affiliation":[{"name":"*Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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