Update on Prodrugs Research at Sunderland University

Sunderland University has given us an update on their research into the use of prodrugs as a treatment for cystinosis:

Summary of Cystinosis Research at the University of Sunderland – Winter/Spring 2014

Research at the University of Sunderland focuses on using prodrugs to improve the treatment for cystinosis. A prodrug is an inactive form of a drug. Once inside the body, the prodrug is broken down to release the active drug; they can be designed to break down in the particular part of the body where they are most needed. Cysteamine prodrugs were designed to overcome some of the problems associated with cysteamine as a treatment for cystinosis.

One of the biggest problems with cysteamine is caused by its rapid metabolism in the body, meaning that large frequent doses are needed because so much is wasted. The unpleasant properties of cysteamine would be more tolerable if a smaller dose could be taken. Our prodrugs are designed to target cells and break down to release cysteamine only after entering the cells, avoiding the problem of wastage due to metabolism. The prodrugs can be broken down by enzymes known to be present in cells and will release the cysteamine gradually over a period of time. We hope this means that smaller and less frequent doses may be required, causing fewer side effects. A reduction in halitosis is also anticipated, as there will be less cysteamine in the blood and so less metabolism of cysteamine to smelly products. The prodrugs were also designed to have an improved taste and smell and to cause less gastric irritation.

A number of prodrugs were designed and synthesised, and then tested in several different laboratory experiments to identify the best ones to take forward.

1. All of the prodrugs were assessed to see how toxic they were to healthy human cells and cystinotic human cells grown in a laboratory. A number of the prodrugs were found to have very low toxicity to all cells, some being even less toxic than cysteamine.
2. The least toxic prodrugs were evaluated to see if they could enter into a range of cell types and then break down to release cysteamine. Using a technique called HPLC (high performance liquid chromatography), we were able to measure the amount of cysteamine released in the cells; we concluded that the prodrugs were readily taken into cells and broken down by enzymes to release cysteamine.
3. Finally, we used cystinotic skin cells, originally from a patient with cystinosis, which have high levels of cystine. We treated these cells with the prodrugs and found that the prodrugs not only depleted cystine to a very low level, but kept the cystine levels lower and for longer than was achieved by treatment with the same amount of cysteamine.

Following these positive tests, we have two prodrugs which may be possible candidates and are being progressed to further testing. If all goes well, we hope to secure European funding during 2015 for pre-clinical and clinical trials.

We are also working on some different prodrugs for the treatment of ocular symptoms. These are designed to improve stability of the drug, so that it is easier to handle and lasts for longer, and to increase uptake of the drug into the eye, which will then break down and release cysteamine gradually in the eye. Hopefully, this will reduce the amount of times the medicine needs to be applied. Currently, we are testing to see if these new prodrugs improve uptake into commercially sourced rabbit eye cells before breaking down to release cysteamine.

We would like to take this opportunity to express our gratitude to the Cystinosis Foundation UK. This work could not be carried out without this support. In addition, we would like to acknowledge the support and expert contributions of Professors Elena Levtchenko and Corrine Antignac.