Finding drugs for primary hyperoxaluria
The liver cells of PH-1 patients cannot convert glyoxylate to glycinewhich causes the formation and accumulation of insoluble oxalate crystals. The kidneys cannot excrete this waste product and this ultimately causes multiple organ failure.The EU-funded project 'New drugs for the treatment of primary Hiperoxaluria' (PH-1) was initiated to develop therapeutic solutions for PH-1. A main focus of the research was the suppression of the enzyme glycolate–oxidase (GO) to prevent formation of glyoxylate using a strategy called substrate reduction therapy (SRT).Studies on genetically modified mice revealed GO as a relatively harmless SRT technique for treating PH-1. Scientists have also successfully unravelled the structure of both human and mouse GO, enabling the design of effective small molecules for GO inhibition. These would be useful in the development of drugs for PH-1 and other diseases that are a result of oxalate accumulation.Project members prepared several small molecules with promising GO inhibitory activity and biological testing is ongoing. Suitable neuroprotective and cytotoxicity assays were developed by one of the project collaborators. Biological screening revealed that some of these compounds also have neuroprotective ability and are non-cytotoxic.Successful project activities could lead to the development of effective therapy for PH-1 patients and vastly improve their quality of life. Commercialisation of such life-saving drugs could reduce health care expenses arising from frequent health care check-ups and obviate the need for liver and kidney transplants.
