Intranasal delivery of Thyroid hormones in MCT8 deficiency

Abstract

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.

Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

“…Although both TH analogs have already been tested in different model systems [ 15 , 16 , 19 , 23 , 24 , 25 , 26 , 27 ], previous studies did not allow to draw any conclusions as to which of the two compounds exerts stronger beneficial effects on CNS development due to a variety of confounding factors (i.e., usage of different Mct8 mutants, treatment regimens, read-out parameters, and drug concentrations). The major aim of our study was, therefore, to evaluate and directly compare the thyromimetic potential of Ditpa and Triac in Mct8/Oatp1c1 double knock-out (Dko) mice as a preclinical AHDS model.…”

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

“…Assuming that permeation into the brain is the key problem in MCT8 deficiency, previous studies have attempted to circumvent the blood–brain barrier by administering TH or TH analogues intranasally or intracerebroventricularly, but with limited success. 9 , 39 , 40 Apparently, endothelial MCT8 is highly efficient in supplying the CNS with TH. After THs enter the CNS through MCT8, uptake in glia or neurons may occur through other transporters, including MCT10, L-type amino acid transporters (LATs), or OATP1C1.…”

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

“…Although both TH analogs have already been tested in different model systems (15,16,19,(26)(27)(28)(29)(30), previous studies did not allow to draw any conclusions as to which of the two compounds exerts stronger beneficial effects on CNS development due to a variety of confounding factors (i.e. usage of different Mct8 mutants, treatment regimens, read-out parameters and drug concentrations).…”