Improving Cystinosis Treatments

Dr Roz Anderson, Sunderland Pharmacy School – Drug Design and Discovery, University of Sunderland.

Cysteamine (now formulated and marketed as Cystagon®) is a lifesaver and its contribution to improving the prognosis and quality of life for cystinotic patients cannot be under-estimated. In fact, when the structure and mode of action of cysteamine is considered, we cannot currently substitute this simple molecule for anything else, we can only try to improve it.

Cystagon® can cause side effects, such as unpleasant breath and body odour, nausea, vomiting, loss of appetite, fever, diarrhoea, drowsiness, rash, dehydration, high blood pressure, abdominal discomfort, gastroenteritis, effects on the nervous system (headaches, nervousness, depression, and, rarely, fits and hallucinations), allergic-type rash and effects on the kidney. These unpleasant symptoms cause some patients to delay or even refuse one or more of their four daily doses.

Once absorbed, and before it can exert its therapeutic effect, a significant amount of the initial cysteamine dose is excreted in the urine or bile and a further amount suffers from metabolism in the liver. This has the effect of decreasing the dose available for treating cystinosis and requires that high and frequent doses of cysteamine be administered, leading to some severe systemic side effects due to the high concentrations of cysteamine after an oral dose.

Sunderland teamThe Sunderland Team pictured (left to right):
Dr Roz Anderson, Prof. Paul Groundwater, Mr Pratap Surydevara

Overall, then, cysteamine offers hope and relative health to cystinotic patients, but does have some inherent problems.

At the University of Sunderland, we are working on cysteamine prodrugs. Prodrugs are inactive forms of a drug, which release the drug by a natural process after administration; this usually involves the action of enzymes in the body. The prodrug approach is not a new concept – there are quite a number of prodrugs already used clinically for a wide variety of diseases, infections and disorders, such as Bambuterol (for asthma), Pivampicillin (for bacterial infections) and Dipivefrine (for glaucoma).

With the support of the Cystinosis Foundation UK, who currently sponsor a PhD student at Sunderland, we have made a number of cysteamine prodrugs for evaluation as treatments for cystinosis. Our prodrugs are designed to

  • have no taste or smell.
  • be absorbed unchanged as the prodrug form.
  • release the full amount of cysteamine efficiently once in the blood.
  • There are significant advantages to this approach. As cysteamine itself will not pass through the liver directly after absorption, we expect that the metabolism and excretion will be reduced, resulting in more of the cysteamine being available for its therapeutic action. This may allow lower and less frequent doses to be effective.

    In another approach, we are using prodrugs to optimise delivery of cysteamine to the cells that most require treatment. For this, a different series of cysteamine prodrugs have been synthesised that are targeted directly to cystinotic cells. These prodrugs will not release cysteamine until they are inside the cystinotic cells, so that no cysteamine will be wasted and there will be a much-reduced risk of side effects.

    The initial results with these compounds were encouraging – they have good cystine-depleting activity when tested against isolated cystinotic cells. We are currently making more of these prodrugs to evaluate in a range of different tests to help identify the most promising candidates to proceed to pre-clinical and clinical testing.

    The most important aspect before candidate prodrugs can proceed to clinical testing is the study of the depletion of cystine from cultured cystinotic cells. This part of the project will be carried out in the USA in collaboration with international cystinosis experts, subject to adequate funding being acquired – we are currently in discussion with the Cystinosis Research Network for this purpose. From there, we hope to start clinical evaluation of the best candidate prodrugs in collaboration with an appropriate industrial partner.

    In summary, this medicinal chemistry research at Sunderland involves the careful design of prodrugs for efficiency and safety. A range of prodrug designs are being made for a preliminary screening of their properties, to choose those with the best overall profile. The best five or six of these prodrugs will be evaluated in various in vitro tests to ensure that they have the desired properties of taste/smell, absorption from the GI tract, release of cysteamine, cystine-depleting ability, and targeting profile (if appropriate) before they move onto to the expensive toxicity testing, pre-clinical and clinical trials. Precise work carried out to optimise the prodrugs at this early stage can prevent the waste of time and money later.

    At Sunderland, we are focused upon achieving an improved treatment based on the successful cysteamine for the benefit of cystinotic patients in the future.

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