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Targeting for success: Mechanistic insights into microRNA-based gene therapy for Huntington disease

  • M. Sogorb Gonzalez
donderdag 9 februari 2023
Rapenburg 73
2311 GJ Leiden


  • Prof.dr. S.J.H. van Deventer

Huntington Disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in the exon 1 of the huntingtin (HTT) gene. This mutation is translated into a polyglutamine tract in the mutant HTT protein which confers a toxic gain-of-function inducing 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 effective 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). AAV-miHTT treatment has previously demonstrated efficacy and safety in reducing mutant HTT protein and rescuing HD phenotype in several HD murine models, in transgenic minipigs, and in HD patient-derived cells. However, mechanism of action studies are still limited.

The work in this thesis describes novel mechanistic features of AAV-miHTT treatment for HD, including the reduction of toxic HTT fragments, the therapeutic spread of engineered miRNAs between neuronal cells mediated by extracellular vesicles and the development of translational biomarkers to monitor its efficacy in the affected brain regions.

These findings support the translation of AAV-miHTT to the clinic and potentially contribute to the development of therapies for HD and other neurodegenerative diseases.


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