Development of T3-peptide ligands to treat MCT8 deficiency via a Trojan horse like mechanism

甲状腺激素转运蛋白MCT 8的失活突变会导致严重的智力和运动迟缓，这种疾病被称为Allan-Herndon-Dudley综合征。到目前为止，没有可用的药物治疗，因为用L-甲状腺素进行额外的替代以克服转运蛋白抵抗或用甲状腺激素衍生物DITPA治疗并没有改善儿童的灾难性神经认知结果。为了克服MCT 8缺乏症中大脑的甲状腺激素抵抗，我们提出了一种新的治疗策略，即利用配体激活的G蛋白偶联受体（GPCR）的内化过程。初步数据显示，T3与肽-GPCR-配体（胰高血糖素样肽1，GLP 1）的结合物可被内化，随后释放至其细胞内受体。在拟议的项目中，我们打算开发这种特洛伊木马机制的甲状腺激素转运与GPCR及其各自的配体作为治疗策略的MCT 8缺乏症。最初，我们将通过可用的T3-GLP 1-偶联物测试其拯救T3转运到MCT 8缺陷细胞和MCT 8缺陷小鼠模型中的能力来证明这一概念。同时，我们将使用124 I-甲状腺激素示踪剂进行成像研究，以确定主要缺乏T3的MCT 8缺陷脑区域。作为初始候选物，我们将进一步测试那些与GPCR结合的T3肽缀合物，其在皮质和基底神经节中普遍表达并且已经显示出通过血脑屏障，例如加压素1a受体V1 Ra配体和δ-阿片受体配体。我们的预期研究将为进一步的临床研究奠定基础，最终证明这一新概念可以挽救MCT 8缺乏症患者的T3转运到大脑中。

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.