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Establishing preclinical proof-of-concept of gene therapy for Huntington disease
Miniariková, J. ; Juhás, Štefan ; Caron, N. ; Spronck, L. ; Vallés, A. ; De Haan, M. ; Blits, B. ; Ellederová, Zdeňka ; van Deventer, S. ; Petry, H. ; Southwell, A. ; Déglon, N. ; Motlík, Jan ; Konstantinová, P. ; Evers, M.
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene. The translated expanded polyglutamine repeat in the huntingtin protein is known to cause toxic gain-of-function, affecting numerous cellular processes. Our approach involves a new therapeutic modality by developing a single (one-time) treatment for HD based on a gene therapy lowering the expression of the toxic huntingtin using the RNA interference (RNAi) mechanism. Huntingtin lowering is achieved using gene transfer of a cassette encoding an engineered microRNA targeting human HTT, delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT).
AAV-mediated delivery in large animals
Blits, B. ; De Haan, M. ; Evers, M. ; Spronck, E. A. ; Motlík, Jan ; Bohuslavová, Božena ; Ellederová, Zdeňka ; Lewis, O. T. ; Johnson, D. ; Woolley, M. ; Gill, S. ; van Deventer, S. ; Konstantinová, P. ; Petry, H.
Gene therapy is an attractive option for treatment of neurological diseases. Delivery of the therapeutic gene at the proper location is key for an effective treatment and remains challenging, especially in larger animals. For translation from smaller (rodents) to larger animals, dimensions are different, but also the immune system plays a more prominent role in larger animals. Direct intracranial parenchymal infusions usually result in local transduction of tissue, whereas intrathecal infusions result in a more widespread transduction in the brain. Depending on the indication, the desired expression pattern of the therapeutic gene is to be elucidated and is dictating the route of infusion.