دورية أكاديمية
Quantifying mutant huntingtin protein in human cerebrospinal fluid to support the development of huntingtin-lowering therapies
| العنوان: | Quantifying mutant huntingtin protein in human cerebrospinal fluid to support the development of huntingtin-lowering therapies |
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| المؤلفون: | Stephanie Vauleon, Katharina Schutz, Benoit Massonnet, Nanda Gruben, Marianne Manchester, Alessandra Buehler, Eginhard Schick, Lauren Boak, David J. Hawellek |
| المصدر: | Scientific Reports, Vol 13, Iss 1, Pp 1-17 (2023) |
| بيانات النشر: | Nature Portfolio, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Medicine LCC:Science |
| مصطلحات موضوعية: | Medicine, Science |
| الوصف: | Abstract Huntington’s disease (HD) is caused by a cytosine adenine guanine-repeat expansion in the huntingtin gene. This results in the production of toxic mutant huntingtin protein (mHTT), which has an elongated polyglutamine (polyQ) stretch near the protein’s N-terminal end. The pharmacological lowering of mHTT expression in the brain targets the underlying driver of HD and is one of the principal therapeutic strategies being pursued to slow or stop disease progression. This report describes the characterisation and validation of an assay designed to quantify mHTT in the cerebrospinal fluid of individuals with HD, for use in registrational clinical trials. The assay was optimised, and its performance was characterised with recombinant huntingtin protein (HTT) varying in overall and polyQ-repeat length. The assay was successfully validated by two independent laboratories in regulated bioanalytical environments and showed a steep signal increase as the polyQ stretch of recombinant HTTs pivoted from wild-type to mutant protein forms. Linear mixed effects modelling confirmed highly parallel concentration–response curves for HTTs, with only a minor impact of individual slopes of the concentration–response for different HTTs (typically |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2045-2322 |
| العلاقة: | https://doaj.org/toc/2045-2322Test |
| DOI: | 10.1038/s41598-023-32630-4 |
| الوصول الحر: | https://doaj.org/article/bad2f4a1d56e443989a5c40b6c57ac69Test |
| رقم الانضمام: | edsdoj.bad2f4a1d56e443989a5c40b6c57ac69 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20452322 |
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| DOI: | 10.1038/s41598-023-32630-4 |