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

Sundaram, S. M.; Arrulo Pereira, A.; Köpke, H.; Müller-Fielitz, H.; Angelis, M. D.; Müller, T. D.; Heuer, H.; Körbelin, J.; Krohn, M.; Mittag, J.; Nogueiras, R.; Prevot, V.; Schwaninger, M.

doi:10.1101/2021.12.05.471343

bioRxiv · 10.1101/2021.12.05.471343

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

Sundaram, S. M.·Arrulo Pereira, A.·Köpke, H.·Müller-Fielitz, H.·Angelis, M. D.·Müller, T. D.·Heuer, H.·Körbelin, J.·Krohn, M.·Mittag, J.·Nogueiras, R.·Prevot, V.·Schwaninger, M.

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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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Sundaram, S. M., Arrulo Pereira, A., Köpke, H., Müller-Fielitz, H., Angelis, M. D., Müller, T. D., Heuer, H., Körbelin, J., Krohn, M., Mittag, J., Nogueiras, R., Prevot, V., Schwaninger, M.. 2021-12-09. Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency. https://doi.org/10.1101/2021.12.05.471343

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