Project Details
Projekt
Development of T3-peptide ligands to treat MCT8 deficiency via a Trojan horse like mechanism
Subject Area
Endocrinology, Diabetology, Metabolism
Term
from 2015 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 280246591
Inactivating mutations in the thyroid hormone transporter MCT8 lead to severe mental and motor retardation, a disease known as the Allan-Herndon-Dudley-Syndrome. So far, no medical treatment is available since additional substitution with L-thyroxin in the aim to overcome transporter resistance or treatment with the thyroid hormone derivate DITPA did not improve the disastrous neurocognitive outcome of the children. To overcome thyroid hormone resistance of the brain in MCT8 deficiency we propose a new treatment strategy by utilizing the internalization process of ligand activated G-protein coupled receptors (GPCR). Preliminary data show, that a conjugate of T3 tethered to a peptide-GPCR-ligand (glucagon-like peptide 1, GLP1) can be internalized and is subsequently released to reach its intracellular receptor. In the proposed project we intend to develop this TROJAN HORSE mechanism of thyroid hormone transport with GPCRs and their respective ligands as a treatment strategy for MCT8 deficiency. Initially we will proof the concept with the available T3-GLP1-conjugate testing its capability to rescue T3 transport into MCT8 deficient cells and MCT8 deficient mice model. In parallel we will perform imaging studies with a 124I-thyroid hormone tracer to identify those regions of MCT8 deficient brain that are predominantly devoid of T3. As initial candidates we will further test those T3-peptide-conjugates that bind to GPCR that are expressed ubiquitously in the cortex and basal ganglia and that were already shown to pass the blood brain barrier, e.g. the vasopressin 1a receptor V1Ra ligands and delta-opioid receptor ligands. Together, our intended studies will lay the ground for further clinical studies that will eventually proof this new concept for rescuing T3 transport into the brain in patients suffering from MCT8 deficiency.
DFG Programme
Priority Programmes
