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

开发 T3 肽配体通过特洛伊木马机制治疗 MCT8 缺陷

• 批准号: 280246591
• 负责人: Professor Dr. Heiko Krude
• 金额: --
• 依托单位: Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280246591?language=en
• 关键词: Development; T3; peptide; ligands; treat

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.

甲状腺激素转运体MCT8的失活突变会导致严重的精神和运动发育迟缓，这种疾病被称为艾伦-赫恩登-达德利综合征。到目前为止，还没有可用的药物治疗，因为为了克服转运蛋白抵抗而额外使用L-甲状腺素替代，或者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果。为了克服MCT8缺乏症患者的甲状腺激素抵抗，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，与多肽-GPCR-配体(GLP1)相连的T3的结合物可以被内化，随后被释放到它的细胞内受体。在拟议的项目中，我们打算开发这种带有GPCRs及其各自配体的甲状腺激素运输特洛伊木马机制，作为治疗MCT8缺乏症的策略。首先，我们将用现有的T3-GLP1结合物来验证这一概念，测试其拯救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成像研究，以确定MCT8缺陷大脑中主要缺乏T3的区域。作为最初的候选，我们将进一步测试那些与GPCR结合的T3-多肽结合物，这些结合物在皮质和基底节普遍表达，并且已经被证明可以通过血脑屏障，例如血管加压素1a受体V1ra配体和增量阿片受体配体。总之，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将挽救MCT8缺乏症患者的T3运输进入大脑。