Extending Mironid's PDE4 activator programme: Hyperparathyroidism as a second clinical indication

人类甲状旁腺激素(PTH)是由位于颈部的四个甲状旁腺产生的，通过控制尿液的重吸收、消化道的吸收和骨骼中的钙库吸收来调节血液中的钙和磷水平。甲状旁腺机能亢进症导致甲状旁腺激素过度释放到血液中，是最常见的内分泌疾病之一，通常由一个或多个甲状旁腺的良性肿瘤或慢性肾脏疾病的继发性后果引起。如果不进行治疗，甲状旁腺功能亢进症患者的甲状旁腺激素慢性升高会导致各种虚弱的症状，当血液中的钙水平高得令人无法接受时，甚至会危及生命。由于肥胖症、糖尿病和相关肾脏疾病的发病率上升，甲状旁腺功能亢进症的患病率正在上升。由斯特拉斯克莱德大学和赫里奥特-瓦特大学的研究团队创立的格拉斯哥生物技术公司Mironid开发出了第一种激活特定酶的分子，称为PDE4长亚型，通常会降解重要的信号分子cAMP。CAMP通常受到非常严格的调控，但在甲状旁腺功能亢进症中，由于甲状旁腺激素的过度刺激，肾脏和骨骼中的某些位置会产生过量的cAMP。Mironid的创新提供了一种新的方法，通过增加cAMP的降解，从而减少cAMP信号，并允许更好地管理甲状旁腺功能亢进症的症状和病理，提供了一种在肾脏和骨骼的PTH作用部位靶向甲状旁腺功能亢进症的新方法。该提案旨在建立在之前成功的Innovate UK BMC资助的Mironid项目(2017年：项目编号：102841)的基础上，该项目已经在治疗另一种肾脏疾病-常染色体显性多囊肾病方面取得了重要进展，该疾病也是由cAMP信号缺陷引起的。作为当前提议的一部分，新分子将在甲状旁腺机能亢进症的翻译模型中进行测试，并将在分析中进行分析，以确定最适合进行高级测试的分子，并最终进入人类试验，最早可能在2025年开始。

Human parathyroid hormone (PTH) is produced by four parathyroid glands located in the neck and regulates the level of calcium and phosphate in the blood by controlling reabsorption from urine, uptake from the digestive tract and resorption from calcium reservoirs in the bone.Hyperparathyroidism results in excessive release of parathyroid hormone into the blood and is one of the most common endocrine disorders, often caused by either a benign tumour in one or more parathyroid glands or as a secondary consequence of chronic kidney disease. Left untreated, the chronic elevation of PTH in hyperparathyroidism causes a variety of debilitating symptoms and can even become life-threatening when the levels of calcium in the blood become unacceptably high. The prevalence of hyperparathyroidism is increasing as a consequence of rising rates of obesity, diabetes and associated kidney disease.Mironid, a Glasgow based biotech company founded by research teams from Strathclyde and Heriot-Watt Universities, has developed the first molecules that activate particular enzymes called PDE4 long isoforms that normally degrade an important signalling molecule called cAMP. cAMP is usually very tightly regulated but in hyperparathyroidism is over produced in certain locations within the kidney and bone as a result of excessive stimulation by PTH. Mironid's innovation offers a novel approach to targeting hyperparathyroidism at the site of PTH action in the kidney and bone, by increasing the degradation of cAMP, thereby reducing cAMP signalling and allowing better management of the symptoms and pathology of hyperparathyroidism.This proposal aims to build upon a previous successful Innovate UK BMC funded Mironid project (Year 2017: Project No: 102841) that has already resulted in important progress towards treating another kidney disease, Autosomal Dominant Polycystic Kidney Disease, also caused by defective cAMP signalling. As part of this current proposal, new molecules will be tested in translational models of hyperparathyroidism and will be profiled in assays to identify the most appropriate molecule for advanced testing and ultimately for progression into human trials which could begin as early as 2025\.