{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:09Z","timestamp":1787018349009,"version":"build-2736575974"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,24]]},"abstract":"<jats:p>\n                    We have developed an inducible Huntington\u2019s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant huntingtin (m\n                    <jats:italic>Htt<\/jats:italic>\n                    ) expression. We asked whether moderate global lowering of m\n                    <jats:italic>Htt<\/jats:italic>\n                    (~50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering (before measurable deficits) was required. Both early and late m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow-up revealed that the benefits, in all m\n                    <jats:italic>Htt-<\/jats:italic>\n                    lowering groups, attenuated by 12 months of age. While early m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12 months of age, and late m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering did not ameliorate striatal transcriptional dysregulation at 12 months of age. Only early m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule\n                    <jats:italic>HTT<\/jats:italic>\n                    -lowering therapeutics progress to the clinic, our findings suggest that moderate m\n                    <jats:italic>Htt<\/jats:italic>\n                    lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of m\n                    <jats:italic>HTT<\/jats:italic>\n                    lowering required to sustain long-term benefits in humans.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.161769","type":"journal-article","created":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T14:00:56Z","timestamp":1666533656000},"source":"Crossref","is-referenced-by-count":27,"title":["Benefits of global mutant huntingtin lowering diminish over time in a Huntington\u2019s disease mouse model"],"prefix":"10.1172","volume":"7","author":[{"given":"Deanna M.","family":"Marchionini","sequence":"first","affiliation":[{"name":"CHDI 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