{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:07:15Z","timestamp":1792145235826,"version":"4.4.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,11,6]]},"abstract":"<jats:p>\n                    Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (\n                    <jats:italic>HTT<\/jats:italic>\n                    ) gene. Although several palliative treatments are available, there is currently no cure and patients generally die 10\u201315 y after diagnosis. Several promising approaches for HD therapy are currently in development, including RNAi and antisense analogs. We developed a complementary strategy to test repression of mutant\n                    <jats:italic>HTT<\/jats:italic>\n                    with zinc finger proteins (ZFPs) in an HD model. We tested a \u201cmolecular tape measure\u201d approach, using long artificial ZFP chains, designed to bind longer CAG repeats more strongly than shorter repeats. After optimization, stable ZFP expression in a model HD cell line reduced chromosomal expression of the mutant gene at both the protein and mRNA levels (95% and 78% reduction, respectively). This was achieved chromosomally in the context of endogenous mouse\n                    <jats:italic>HTT<\/jats:italic>\n                    genes, with variable CAG-repeat lengths. Shorter wild-type alleles, other genomic CAG-repeat genes, and neighboring genes were unaffected. In vivo, striatal adeno-associated virus viral delivery in R6\/2 mice was efficient and revealed dose-dependent repression of mutant\n                    <jats:italic>HTT<\/jats:italic>\n                    in the brain (up to 60%). Furthermore, zinc finger repression was tested at several levels, resulting in protein aggregate reduction, reduced decline in rotarod performance, and alleviation of clasping in R6\/2 mice, establishing a proof-of-principle for synthetic transcription factor repressors in the brain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1206506109","type":"journal-article","created":{"date-parts":[[2012,10,11]],"date-time":"2012-10-11T08:04:29Z","timestamp":1349942669000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":179,"title":["Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6\/2 mice"],"prefix":"10.1073","volume":"109","author":[{"given":"Mireia","family":"Garriga-Canut","sequence":"first","affiliation":[{"name":"EMBL\/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain;"},{"name":"Universitat Pompeu Fabra (UPF), 08003 Barcelona, 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