Prodrugs Research at University of Sunderland

Our thanks go to Professor Roz Anderson, at Sunderland University, for providing us with a recent update on her team’s research into prodrugs that are hoped to deliver improved treatments for cystinosis. This is a project for which the Cystinosis Foundation UK is providing funding.

Prodrugs Research at University of Sunderland, Prof Roz Anderson, January 2012

Just before Christmas 2011, PhD student, Mrs Lisa Frost, obtained the key results for which we were hoping: the 4 lead prodrugs we had identified as being of lowest possible toxicity showed excellent cystine depleting activity. In fact, not only did they perform as well as Cysteamine in a test on cultured cystinotic cells in the laboratory, they kept the level of cystine well below the target of 1.0 nmol cystine/mg protein1 for a much longer time period, suggesting that fewer daily doses could be a possibility.

In the graph below, you can see the orange line with round points showing the levels of cystine as a result of treating cystinotic skin cells with cysteamine and other coloured lines show the levels of cystine after treatment with one of five test prodrugs; all prodrugs and cysteamine were used at a concentration of 20 x 10-6mol/L (20 μM). We chose this concentration as it is believed to be the lowest concentration of cysteamine in the body that is effective in treating patients; we wanted to compare the prodrugs to cysteamine at a clinically realistic concentration.

The graph shows the time of treatment along the bottom and the concentration of cystine found in the cystinotic cells vertically: the higher a point, the more cystine was present. At the start at time 0, the concentration of cystine was found to be about 2.5 nmol cystine/mg protein, which confirms that all of the cells we used had similar amounts of cystine accumulation and that it was at a higher level than would be seen in a non-cystinotic cell. Each of the five prodrugs is represented by different symbols and differently coloured lines. The lilac coloured dotted horizontal line marks the target level of 1.0 nmol cystine/mg protein for reference; the aim was to get the level of cystine below this lilac coloured line. There are two main points to note from the figure:

  1. All of the prodrugs reduce the level of cystine to well below the target level in around 2-3 hours;
  2. All of the prodrugs reduce the level of cystine over an extended time period; they all maintain the cystine level below the target for over 12 hours and some achieve this for a longer period.

Coupled with our previous results on toxicity of the test prodrugs, we believe that the 4 lead prodrugs are suitable to progress further. We are now doing some other experiments to check several important aspects and are in discussion with Dr Corinne Antignac in Paris, who developed a mouse model of cystinosis; we hope to start testing our 4 lead prodrugs for their efficacy at depleting cystine levels in cystinotic mice in the future.

Cystine Depletion - Results From Sunderland University

1The target level of cystine has been previously reported as 0.5 nmol cysteine/mg protein, but has recently changed to 1.0 nmol cystine/mg protein.

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