Endocrine Abstracts

Inactivating mutations in the thyroid hormones (TH) transporter monocarboxylate transporter 8 (MCT8) lead to the X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome (AHDS). AHDS pathophysiology is characterized by peripheral hyperthyroidism and cerebral hypothyroidism, which results in severe neurological impairments. Although AHDS leads to a spectrum of severe endocrine and neurological alterations, treatment options for MCT8-deficient patients are limited, and none have been able to prevent or effectively ameliorate the neurological impairments. Other than the complex symptomatology exhibited by patients, additional problems in the search for therapies for AHDS stem from the early onset of its alterations. In humans, CNS histopathological features have been found as early as in the fetal stages. In this context, treatment in postnatal stages, even if it was able to recover TH status and impede further alterations from happening, may not be enough to recover alterations happening from fetal stages. Thus, the aim of this work was to find and evaluate an effective therapeutic option from the earliest possible stage. This study explored the effects of the TH-analog sobetirome and its CNS-selective amide prodrug, Sob-AM2, in the treatment of pregnant dams carrying fetuses lacking Mct8 and deiodinase type 2 (Mct8/Dio2 KO), as a murine model for MCT8 deficiency. Pregnant dams carrying Mct8/Dio2 KO fetuses were treated with sobetirome or Sob-AM2 for 7 days, starting at embryonic day 12.5 (E12.5). Dams’ body weight over pregnancy and TH levels were measured. Then, the effect of treatments on the expression of TH-dependent genes was measured in the placenta, fetal liver, and fetal cerebral cortex. Maternal sobetirome treatment led to spontaneous abortions and fetal malformations. Sob-AM2 treatment, however, revealed no apparent harmful effects. Moreover, gene expression analysis revealed that Sob-AM2 crossed effectively the placental as well as the brain barriers and was found to exert thyromimetic effects in Mct8/Dio2 KO fetal tissues. Sob-AM2 treatment mediated thyromimetic effects in the fetal liver by increasing the expression of deiodinases, while in the brain it was able to increase the expression of several T3-dependent genes in Mct8/Dio2 KO fetuses. Our data demonstrate that maternal administration of Sob-AM2 can cross the placental barrier and access the brain and other fetal tissues, in MCT8-deficiency to exert thyromimetic actions by modulating TH-target gene expression. These observations thus indicate that Sob-AM2 has the potential to prevent neurodevelopmental alterations in the MCT8-deficient fetal brain by addressing cerebral hypothyroidism, hence representing a promising option for AHDS patients.