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Exon 1-targeting miRNA reduces the pathogenic exon 1 HTT protein in Huntington's disease models.
Brain
December 2024
Department of Research & Development, uniQure Biopharma BV, Amsterdam 1105 BP, The Netherlands.
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT) that results in toxic gain of function and cell death. Despite its monogenic cause, the pathogenesis of HD is highly complex, and increasing evidence indicates that, in addition to the full-length (FL) mutant HTT protein, the expanded exon 1 HTT (HTTexon1) protein that is translated from the HTT1a transcript generated by aberrant splicing is prone to aggregate and might contribute to HD pathology. This finding suggests that reducing the expression of HTT1a might achieve a greater therapeutic benefit than targeting only FL mutant HTT.
View Article and Find Full Text PDFAAV5-miHTT-mediated huntingtin lowering improves brain health in a Huntington's disease mouse model.
Brain
June 2023
Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia and BC Children's Hospital, Vancouver, BC V5Z4H4, Canada.
Huntingtin (HTT)-lowering therapies show great promise in treating Huntington's disease. We have developed a microRNA targeting human HTT that is delivered in an adeno-associated serotype 5 viral vector (AAV5-miHTT), and here use animal behaviour, MRI, non-invasive proton magnetic resonance spectroscopy and striatal RNA sequencing as outcome measures in preclinical mouse studies of AAV5-miHTT. The effects of AAV5-miHTT treatment were evaluated in homozygous Q175FDN mice, a mouse model of Huntington's disease with severe neuropathological and behavioural phenotypes.
View Article and Find Full Text PDFFunctional Intercellular Transmission of miHTT via Extracellular Vesicles: An In Vitro Proof-of-Mechanism Study.
Cells
September 2022
Department of Research and Development, uniQure Biopharma B.V., 1105 BP Amsterdam, The Netherlands.
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by GAG expansion in exon 1 of the huntingtin () gene. AAV5-miHTT is an adeno-associated virus serotype 5-based vector expressing an engineered HTT-targeting microRNA (miHTT). Preclinical studies demonstrate the brain-wide spread of AAV5-miHTT following a single intrastriatal injection, which is partly mediated by neuronal transport.
View Article and Find Full Text PDFIntrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology.
Brain Sci
January 2021
Madeha Management & Consultancy, 1222 LM Nederhorst den Berg, The Netherlands.
Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as a key pathological mechanism. There are currently no disease modifying therapies for HD; however, -lowering therapies hold promise. Recombinant adeno-associated virus serotype 5 expressing a microRNA that targets mRNA (AAV5-miHTT) is in development for the treatment of HD with promising results in rodent and minipig HD models.
View Article and Find Full Text PDFAAV5-miHTT gene therapy for Huntington disease: lowering both huntingtins.
Expert Opin Biol Ther
October 2020
Research, uniQure biopharma B.V , Amsterdam, The Netherlands.
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