New drug compound could tackle hereditary kidney disease

An international collaboration of scientists is working to develop a new class of drugs to treat a common genetic kidney disease that is a major cause of kidney failure, with promising results.

Glasgow-based biotech company Mironid has developed a compound to treat autosomal dominant polycystic kidney disease (ADPKD) — a hereditary, progressive disease that affects around 12 million people worldwide. Successful laboratory tests of the compound have now been conducted by researchers at the University of Sheffield and colleagues in the US.

ADPKD is caused by a genetic fault that disrupts the normal development of kidney cells and causes cysts to form inside the kidneys. The cysts grow and eventually destroy normal kidney tissue, causing the kidneys to stop working properly. This leaves patients needing life-saving treatments, such as dialysis or a kidney transplant.

In ADPKD cells, cysts develop and grow because they express higher than normal levels of a ‘messenger molecule’ called cyclic AMP (or cAMP). One of the many known functions of cAMP is to tell cells when to divide and when to secrete fluid. The compound discovered by Mironid activates an enzyme called PDE4, whose natural role is to break down cAMP; the novel small molecule activators of PDE4 enzymes thus act to suppress disease-driving cAMP signalling.

Using cell lines and patient tissues derived from the kidneys of ADPKD patients, researchers at Sheffield and in the US confirmed that when the Mironid compound switched PDE4 on, levels of cAMP in the disease cells were reduced and the number and growth of the cysts were suppressed. Moreover, the reversible nature of the compound means that PDE4 activity may be rapidly and accurately controlled in patients, according to the dose decided by the clinician.

This suggests that a future treatment for ADPKD could be tailored to an individual patient’s needs and the severity of their disease without the side effects seen with other approaches. In theory, the compound could also suppress cyst formation due to ADPKD in other organs apart from the kidney, especially in the liver.

“Drug development usually focuses on looking for ways to block molecular and chemical processes, not switch them on, so this is a rare mode of action,” said Prof Albert Ong, who led the experiments conducted at the University of Sheffield.

“This discovery gives me hope for the many patients I see in my clinics that there could be another effective new treatment in the future to keep the disease in check for much longer, either on its own or in combination with other drugs such as tolvaptan.

“I would love to think that ADPKD could one day be a disease that people can successfully manage throughout their natural lives, rather than one that could shorten their lives.”

The findings so far have been published in the journal Proceedings of the National Academy of Sciences. Mironid’s next step is to refine the compounds in anticipation of being able to develop a new medicine to treat ADPKD patients.

Image credit: ©stock.adobe.com/au/bluebay2014

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