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

人甲状旁腺激素（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钙库的重吸收来调节血液中钙和磷酸盐的水平。甲状旁腺功能亢进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中的良性肿瘤引起，或作为慢性肾脏疾病的继发结果。如果不进行治疗，甲状旁腺功能亢进症中PTH的慢性升高会导致各种衰弱症状，当血液中的钙水平变得不可接受的高时，甚至会危及生命。由于肥胖、糖尿病和相关肾脏疾病的发病率不断上升，甲状旁腺功能亢进症的患病率正在增加。Mironid是一家总部位于格拉斯哥的生物技术公司，由斯特拉斯克莱德大学和赫瑞瓦特大学的研究小组创立，它已经开发出第一种分子，可以激活称为PDE 4长型的特定酶，这种酶通常会降解一种称为cAMP的重要信号分子。cAMP通常受到非常严格的调节，但在甲状旁腺功能亢进症中，由于PTH的过度刺激，在肾脏和骨内的某些位置过度产生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信号传导，从而更好地管理甲状旁腺功能亢进症的症状和病理，将甲状旁腺功能亢进症靶向于肾脏和骨骼中的PTH作用部位。该提案旨在建立在先前成功的Innovate UK BMC资助的Mironid项目的基础上。（2017年：项目编号：102841）已经在治疗另一种肾脏疾病方面取得了重要进展，常染色体显性多囊肾病，也是由cAMP信号传导缺陷引起的。作为当前提案的一部分，新分子将在甲状旁腺功能亢进的翻译模型中进行测试，并将在测定中进行分析，以确定最适合用于高级测试的分子，并最终进入人体试验，该试验最早可能于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\.