RT Journal Article
SR Electronic
T1 Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.05.471343
DO 10.1101/2021.12.05.471343
A1 Sivaraj M. Sundaram
A1 Adriana Arrulo Pereira
A1 Hannes Köpke
A1 Helge Müller-Fielitz
A1 Meri De Angelis
A1 Timo D. Müller
A1 Heike Heuer
A1 Jakob Körbelin
A1 Markus Krohn
A1 Jens Mittag
A1 Ruben Nogueiras
A1 Vincent Prevot
A1 Markus Schwaninger
YR 2021
UL http://biorxiv.org/content/early/2021/12/09/2021.12.05.471343.abstract
AB 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.