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

甲状腺激素转运体MCT8的失活突变会导致严重的智力和运动迟缓，这是一种被称为艾伦-赫恩顿-达德利综合征的疾病。到目前为止，没有可用的药物治疗，因为为了克服转运体抵抗而使用l -甲状腺素替代或使用甲状腺激素衍生物DITPA治疗并没有改善儿童灾难性的神经认知结局。为了克服MCT8缺乏症的甲状腺激素抵抗，我们提出了一种利用配体激活的g蛋白偶联受体（GPCR）内化过程的新治疗策略。初步数据显示，连接到肽- gpcr -配体（胰高血糖素样肽1，GLP1）的T3偶联物可以内化并随后释放到达其细胞内受体。在拟议的项目中，我们打算利用gpcr及其相应的配体开发甲状腺激素运输的特洛伊木马机制，作为MCT8缺乏症的治疗策略。首先，我们将用现有的T3- glp1偶联物来验证这一概念，测试其挽救T3转运到MCT8缺陷细胞和MCT8缺陷小鼠模型的能力。同时，我们将使用124i -甲状腺激素示踪剂进行影像学研究，以确定MCT8缺乏的大脑中主要缺乏T3的区域。作为最初的候选物，我们将进一步测试那些与GPCR结合的t3肽偶联物，这些偶联物在皮层和基底神经节中普遍表达，并且已经被证明可以通过血脑屏障，例如加压素1a受体V1Ra配体和δ阿片受体配体。总之，我们预期的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，挽救T3转运到患有MCT8缺乏症的患者的大脑。

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.