| Přispěvatelé: |
Deventer, S.J. van, Konstantinova, P., Evers, M., Rabelink, A.J., Wijnholds, J., Reits, E.A.J., Kampinga, H.H., Shakalisava, Y., Leiden University |
| Popis: |
Huntington Disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in the exon 1 of the huntingtin (HTT) gene, which confers a toxic gain-of-function inducing protein aggregation and cell death. Although HD has a well-defined monogenic cause and promising HTT-lowering therapies are being tested in clinical trials, mechanism of action studies can reveal relevant information about therapeutic targets and outcomes required for successful translation into patients.One of the most advanced HTT lowering therapies for HD is a micro(mi)RNA-based gene therapy which consists of an engineered miRNA targeting the exon 1 sequence of HTT (miHTT) and delivered by adeno-associated virus (AAV) into neuronal striatal cells (AAV-miHTT).The work in this thesis describes novel mechanistic features of AAV-miHTT treatment for HD, including the targeting of toxic HTT fragments, the therapeutic spread between neuronal cells and the development of translational biomarkers to monitor its efficacy in the affected brain regions. In the light of this work, we support the reduction of HTT exon 1 fragment, the persistent efficacy in most affected brain areas, and mechanisms that improve therapeutic spread to all affected cells, as processes that potentially contribute to the successful treatment of HD patients. |
