A major goal of this Clinical Research Unit is the translation of experimental results into the therapy of polycystic kidney disease. The CRU is uniquely positioned to provide novel concepts for clinical trials directed to combat polycystic kidney disease. Based on their efficacy in animal models of polycystic kidney disease, two drugs, vasopressin-2-receptor antagonists and mTOR inhibitors, are in clinical trials of patients with ADPKD. However, these candidate medications for treatment of cystic kidney disease work through mechanisms that are not well understood. Part C will analyse current therapeutic approaches, address down-stream consequences of de-regulated mTOR signalling, and develop optimized treatment regimens.

Project P7 (T. Wegierski & T. Huber) will determine the impact on cyst formation by activated mTOR and its inhibition of the autophagy pathway. Since the kidney has a relatively high basal level of autophagy, inhibition of this cellular program may severely compromise the adaptive responses of the environmental changes caused by progressive cyst growth. Using the pcy and jck mouse models of polycystic kidney disease in combination with the newly established NPHP3 KO mouse, project P8 will generate novel mouse models of cystic kidney disease to model clinical phenotypes, such as rapid versus slow onset of cyst development. These newly characterized mouse models will be used in project P9 to study the efficacy of pharmacological interventions aimed to slow the progression of polycystic kidney disease. Project P9 is a multi-disciplinary endeavour that involves investigators from Medicine, Radiology, and Medicinal Chemistry to optimize current therapies and test new interventions. In addition, novel markers for disease progression will be developed, for both effective screening of new therapies and assessment of clinical course. And newly identified components of the polycystin and mTOR cascades from Projects P1 and P2 will provide candidate targets for drugs to slow cyst formation. Furthermore, P9 will analyse the expression and function of candidate molecules from projects P1-4 during cyst formation and progression.

In order to intensify the coorperation between university and industry Gerd Walz has recently initiated a clinical trial with Novartis. This trial will test the safety and efficacy of the mTOR inhibitor everolimus (Certican®, Novartis) in 430 patients with autosomal dominant polycystic kidney disease.  Novartis will provide the CRU with blood and urine samples to develop and test novel biomarkers of disease progression. Sanofi-Aventis has kindly provided the vasopressin-2-receptor antagonist SR121463. The CRU will compare the effects of this vasopressin-2-receptor antagonist with mTOR inhibitors, and determine whether the combination of these two medications synergizes to suppress cyst progression. These two components will provide the “gold standard” for assessing the efficacy of novel approaches.