The University of Sheffield, UK, has teamed up with Scottish drug discovery company Mironid to identify and develop drug candidate molecules for the treatment of polycystic disease (PKD). The most common form of this genetic disorder – whereby a child inherits the mutated gene from only one parent – affects ca 12.5m people worldwide.
PKD is characterised by the growth of thousands of fluid-filled cysts in the kidneys. The kidneys gradually enlarge and become deformed, reducing their ability to function. Around 50% of PKD sufferers will have experienced kidney failure by the age of 60, when they will need either a kidney transplant or life-long dialysis. There is no cure and current management is aimed at treating symptoms, ie severe back pain, frequent bladder and kidney infections, high blood pressure and headaches.
Mironid’s approach, led by its founder Miles Houslay, also professor of pharmaceutical innovation at King’s College London, focuses on breaking down cell signalling molecule cyclic adenosine monophosphate (cAMP), the over-production of which plays a role in the formation of the kidney cysts. Specifically, Houslay and his team have identified a family of molecules that are capable of selectively binding to a form of the phosphodiesterase-4 (PDE4), thereby switching the enzyme to its active conformation. In this way, the enzyme can break down cAMP in the cell - removing a major driver for cyst formation.
In collaboration with Albert Ong, professor of renal medicine and his team at the University of Sheffield, the researchers have shown the approach can suppress and even reverse cyst formation in human kidney-derived cells in culture. ‘In laboratory tests we can make human kidney cells grow cysts by adding cAMP to the culture medium,’ Ong explains. ‘Using the drug candidates provided by Mironid, we can show that in the early stages of the disease, the rate of growth of the cysts is inhibited. When we allow the cells to form cysts and then treat them with the proprietary molecules at a later date – mimicking more closely how the disease manifests itself in humans [as] PKD is not usually detected until adult life – we see the cysts get smaller. ’
Mironid has filed UK and international patent applications on its PDE4 modulators. The next stage is to test the drug candidate molecules in animal models. ‘The challenge now lies in finding out whether we can treat animals at various stages of the disease, to find out if the compounds stabilise or cause the cysts to shrink. If this is possible, it holds huge promise for moving into clinical trials in a few years,’ Ong says.