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\.

According to the World Health Organisation 8.8 million people died of cancer in 2015: 1 in 6 of all global deaths. Tumours are able to hide from the immune system, avoiding detection and removal by the body's natural defences. The ability to reveal tumours to the immune system by overcoming cloaking processes, the core of immuno-oncology, is showing great promise in the treatment of cancer. Mironid is applying its unique understanding of cAMP signalling to develop a pioneering approach to immuno-oncology. cAMP signalling within cells is compartmentalised and its elevation in a compartment controlled by cAMP phosphodiesterase-4 (PDE4), which degrades cAMP, and attenuates immune system function. cAMP is a key molecule involved in cell signalling and excessive levels of cAMP can prevent the immune system from attacking tumour cells. Mironid have developed, for the first time, compounds that activate PDE4\. This enhances cAMP degradation in this key compartment removing the brake that holds the immune system back from attacking tumours. We will evaluate PDE4 activators as novel agents for stimulating the immune system to attack tumours. This innovative programme provides an excellent opportunity to improve the effectiveness of cancer treatment and save lives. Sustainable economic impact will be achieved by establishing Mironid as a leading UK pharma company with long term growth prospects and employment benefits.

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening and currently incurable genetic disorder of the kidneys characterised by the development of pathological cysts. It affects some 12.5 million people worldwide, with around 50% of sufferers requiring treatment for kidney failure by the age of 60. Mironid is applying its unique understanding of cellular signalling to develop a pioneering approach to ADPKD therapy, reversing the genetically driven chemical imbalance in the kidneys that drives cyst formation. The project will deliver novel active molecules for rapid optimisation into therapeutics that offer, for the first time, the ability to halt and reverse disease progression in ADPKD. Mironid’s new approach to modulating cellular signalling also has potential for treating a number of other diseases with a high unmet medical need, including both rare and more prevalent diseases. This innovative programme therefore provides an excellent opportunity to transform the treatment options available to patients, improve the cost-effectiveness of the NHS, whilst also maximising sustainable economic impact by further establishing Mironid as a leading UK pharmaceutical company with long term growth prospects and employment benefits.