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Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

Sivaraj M. Sundaram, Adriana Arrulo Pereira, Hannes Köpke, Helge Müller-Fielitz, Meri De Angelis, Timo D. Müller, Heike Heuer, Jakob Körbelin, Markus Krohn, View ORCID ProfileJens Mittag, Ruben Nogueiras, View ORCID ProfileVincent Prevot, Markus Schwaninger
doi: https://doi.org/10.1101/2021.12.05.471343
Sivaraj M. Sundaram
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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Adriana Arrulo Pereira
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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Hannes Köpke
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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Helge Müller-Fielitz
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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Meri De Angelis
2Institute for Diabetes and Obesity, Helmholtz Zentrum Munich, Munich, and German Center for Diabetes Research (DZD), Germany
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Timo D. Müller
2Institute for Diabetes and Obesity, Helmholtz Zentrum Munich, Munich, and German Center for Diabetes Research (DZD), Germany
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Heike Heuer
3Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Jakob Körbelin
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
4Department of Oncology, Hematology and Bone Marrow Transplantation, UKE Hamburg-Eppendorf, Hamburg, Germany
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Markus Krohn
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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Jens Mittag
5Institute for Endocrinology and Diabetes, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
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  • ORCID record for Jens Mittag
Ruben Nogueiras
6Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
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Vincent Prevot
7Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European Genomic Institute for Diabetes (EGID), Lille, France
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Markus Schwaninger
1Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
8DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel, Germany
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  • For correspondence: markus.schwaninger@uni-luebeck.de
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Abstract

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

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  • Conflict-of-interest statement: The authors have declared that no conflict of interest exists.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 09, 2021.
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Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency
Sivaraj M. Sundaram, Adriana Arrulo Pereira, Hannes Köpke, Helge Müller-Fielitz, Meri De Angelis, Timo D. Müller, Heike Heuer, Jakob Körbelin, Markus Krohn, Jens Mittag, Ruben Nogueiras, Vincent Prevot, Markus Schwaninger
bioRxiv 2021.12.05.471343; doi: https://doi.org/10.1101/2021.12.05.471343
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Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency
Sivaraj M. Sundaram, Adriana Arrulo Pereira, Hannes Köpke, Helge Müller-Fielitz, Meri De Angelis, Timo D. Müller, Heike Heuer, Jakob Körbelin, Markus Krohn, Jens Mittag, Ruben Nogueiras, Vincent Prevot, Markus Schwaninger
bioRxiv 2021.12.05.471343; doi: https://doi.org/10.1101/2021.12.05.471343

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