John Terry, Cystinosis Foundation UK
Since 2002 the Foundation has been supporting research in the Pharmacy School at Sunderland University led by Dr Roz Anderson and Prof. Paul Groundwater which is aimed at developing Prodrugs of cysteamine. Cysteamine is the active ingredient in Cystagon, the drug that all cystinotics take.
They are inactive forms of a known drug created by combining the drug with other chemicals that protect it from breakdown until it reaches the sites in the body where it is needed. The really clever part is to get it to breakdown to release the active drug when it gets there.
Unfortunately, as delivered in Cystagon, a high proportion of the drug dose never gets to the cells where it is needed. It is broken down in the liver and is excreted in urine. It also continues to be broken down in the blood, so after 6 to 8 hours it is no longer effective. These are the reasons that a large dose has to be taken so frequently. Since it tastes unpleasant and leads to unpleasant side effects – breath and body odour, nausea and even stomach ulcers – a high, frequent dose is no fun for the patients. The aim of the work is to create taste and odour free compounds carrying the cysteamine into the cells where they are needed.
We have been supporting a Ph.D. student, Pratap Suryadevara, who has been doing the work.
Prodrug candidates have been synthesized and have gone through initial screening. They are being evaluated for their ability to enter kidney cells and to release the cysteamine there. The first candidate has demonstrated that ability.
Collaborations have been put in place with other researchers to quantify the reductions in taste and smell. Next, in collaboration with Dr William Van’t Hoff at Great Ormond Street, all of the candidates will be evaluated in human kidney and skin cells with the successful ones going on to be tested on human cystinotic cells. The best candidates will have their cystine depleting ability quantified in collaboration with Dr Neil Dalton at Guy’s Hospital.