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

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.

Development and validation of an LC-MS/MS methodology for the quantification of thyroid hormones in dko MCT8/OATP1C1 mouse brain

“…Previously, we used a nano-aquity UPLC coupled with a Q-Tof mass detector for TH quantification in several different tissue [ 24 , 25 , 31 , 32 ]. However, when this instrumentation was applied for the measurement of THs in MCT8/Oatp1c1 dko mice, only T3 was quantified [ 33 ]. For this reason an UPLC-system interfaced with a triple-quadrupole (QQQ) mass detector was used for this study.…”

Triac treatment prevents neurodevelopmental and locomotor impairments in thyroid hormone transporter Mct8/Oatp1c1 deficient mice

“…As an alternative to TH analog treatment, gene therapy approaches exploiting AAV vector constructs have been considered (32-34). These interventions aim to express a functional MCT8 transporter in brain endothelial cells and eventually restore TH action in other neural cell types.…”

“…These interventions aim to express a functional MCT8 transporter in brain endothelial cells and eventually restore TH action in other neural cell types. Intravenous injection of endothelial cell specific AAV-BR1-Mct8 constructs in newborn Dko mice resulted in improved cerebellar development, myelination and GABAergic marker expression (34). Yet, these beneficial effects were less profound compared to the alterations seen here upon high dose Triac treatment in Dko mice.…”

“…As an alternative to TH analog treatment, gene therapy approaches exploiting AAV vector constructs have been considered (32)(33)(34) peripheral hyperthyroidism is preserved, while TH-target genes in the CNS showed only a partial response (33).…”

Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

“…We hence conclude that Mct8 / Oatp1c1 dKO mice represent a robust and reliable model organism for the preclinical assessment of drugs designed to treat the AHDS. Underlining the physiological relevance of this model organism for the development of drugs to treat AHDS, viral-mediated central restoration of Mct8 expression increased central T3 levels and improves motor function in Mct8 / Oatp1c1 dKO mice [ 30 , 31 ].…”