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

Sivaraj M Sundaram, Adriana Arrulo Pereira, Helge Müller-Fielitz, Hannes Köpke, Meri De Angelis, Timo D Müller, Heike Heuer, Jakob Körbelin, Markus Krohn, Jens Mittag, Ruben Nogueiras, Vincent Prevot, Markus Schwaninger

Abstract

A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, 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 tri-iodothyronine (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.

Original languageEnglish
JournalBrain : a journal of neurology
Volume145
Issue number12
Pages (from-to)4264-4274
Number of pages11
ISSN0006-8993
DOIs
Publication statusPublished - 19.12.2022

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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