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AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in an Allan-Herndon-Dudley Syndrome mouse model

Year: 2021
Type: preprint
Abstract: Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8 -/y ;Oatp1c1 -/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T 3 -brain content and T 3 -related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.
DOI: 10.1101/2021.10.31.466634
Authors: Xiao-Hui Liao, Pablo Avalos, Oksana Shelest, Raz Ofan, Michael Shilo, Catherine Bresee, Shibi Likhite, Jean-Philippe Vit, Heike Heuer, Brian Kaspar, Kathrin Meyer, Alexandra M. Dumitrescu, Samuel Refetoff, Clive N. Svendsen, Gad D. Vatine
Institutions: University of Chicago, Cedars-Sinai Medical Center, Ben-Gurion University of the Negev, Nationwide Children's Hospital, Abigail Wexner Research Institute, The Ohio State University, University of Duisburg-Essen
Language: English
Subfield: Genetics
Open Access status: green
OpenAlex ID: W3208586522
Cites: 55
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Related to: 10