Cystinosis and its treatment

ARTICLES
CYSTINOSIS AND ITS TREATMENT
By D. Cairns, PhD, MRPharmS, R. J. Anderson, PhD, MRSC,
M. Coulthard, MB ChB, and J. Terry
Cystinosis is a rare inherited disease with an incidence, in developed countries, of about one case in every 200,000 live births. In the past, it was rare for cystinosis sufferers to survive into adulthood. The disease occurs when the mechanism that removes excess cystine breaks down. Cystine then accumulates within body cells preventing these cells from functioning correctly. This initially leads to kidney problems and progresses to other parts of the body, including the thyroid gland, eyes and liver. Impaired growth is yet another symptom of the condition. In this article, the condition and its Nephropathic cystinosis is a rare The disease is caused by a defect in the cystinosis, or may be unrelated to the condi- lysosomal transport mechanism for cystine tion. The daily drug regimen of a typical cystinotic patient is presented in Panel 3.
This patient is post-transplant and is receiv- 115,000 and one in 179,000 live births.1,2 ing, in addition to cysteamine and carnitine, There are approximately 200 patients in the the cystine transport protein, cystinosin.5,6 A number of mutations have been described, itself in raised intracellular levels of the as well as a major deletion present in about The main drug treatment for cystinosis is essential amino acid cystine to 50 to 100 50 per cent of cystinosis patients of Western administration of the aminothiol, cysteamine times normal levels. Crystals of cystine are European ancestry (although cystinosis has (mercaptamine, as the bitartrate salt, Cysta- been described in all major ethnic groups).
rates, leukocytes, cornea and conjunctiva.
The disease is characterised by poor growth, cysteamine-cysteine mixed disulphide within URRENT TREATMENT
cells, which is structurally similar to the amino proximal tubule function), renal glomerular Treatment of cystinosis involves administra- acid lysine and can egress the lysosome using failure and involvement of other tissues and tion of glucose and electrolytes to reverse the pathway for lysine excretion (Figure 1).12 the effects of Fanconi syndrome, as well as Cystinosis is fatal if not treated and death corneal and renal transplant. Indomethacin occurs in the second decade of life. Treat- is administered for its sodium, potassium molecule possesses an offensive taste and ment begun just after birth can attenuate the smell and irritates the gastrointestinal tract, rate of renal failure. However glomerular patients, carnitine is used to combat the effects of muscle weakness brought about by administration. In addition, cysteamine is (approximately one year) is irreversible and urinary loss of free carnitine and subsequent excreted in breath and sweat, which leads to may result in the need for renal transplant.
reduction in the transport of fatty acids into The condition has been recently reviewed.3,4 effects, such as neutropenia. As a result of growth in short children with chronic renal these problems, patient compliance is poor.
Panel 1. Symptoms of
FUTURE TREATMENTS
cystinosis
a cystinosis patient is often considerable, especially when serious medical conditions amine, two recent projects have been estab- such as epilepsy or diabetes, are present.
lished at the University of Sunderland. A into a sustained release form.13 This, it is hoped, will minimise the gastric irritation Panel 2. Treatments
experienced by patients taking large oral for cystinosis
Dr Cairns and Dr Anderson are senior lecturers in the Institute of Pharmacy, Chemistry and Biomedical Sciences, University of Sunderland. Dr Coulthard is a paediatric nephrologist, Royal Victoria Infirmary, Newcastle-upon-Tyne, and Mr Terry is founder and adviser, Cystinosis Foundation UK. Correspondence to Dr Cairns (e-mail donald.cairns@sunderland.ac.uk) ARTICLES
Panel 3. Daily drug
regimen for a typical
patient with cystinosis
Cysteamine bitartrate 750mg tidSodium valproate This patient is post-transplant and is receiv- Figure 1: Structural similarity between (a) lysine and (b) cysteine-cysteamine mixed
ing, in addition to cysteamine and carnitine, disulphide
treatment for epilepsy, diabetes andhypothyroidism teamine. Prodrugs often exhibit desirable improvements over the parent drug, such as ber of cysteamine prodrugs and determined increased lipophilicity (which aids uptake their general cytotoxicity in cultures of expo- cells.14 Preliminary results indicate that none mouse model (an animal with an engineered of the prodrugs tested showed any cell toxicity genetic defect that results in it displaying the USEFUL WEBSITES
up to a concentration of 100mM. These com- symptoms of cystinosis). Study of cystinosis pounds are currently being evaluated for their has long suffered from the lack of a naturally ability to deplete cystine in cultured cystinotic cells. Such research offers hope for the future cystinosis” will enable novel therapies to be of cystinosis sufferers. If successful, the pro- evaluated quickly. The most far ranging and drug approach for cystinosis will target cyste- potentially exciting use for these animals is as a target for gene therapy. Once the mouse drastically reduce side effects and eliminate the need for repeated daily dosing. The devel- opment of prodrugs for cystinosis would be functioning CTNS gene. Successful genetic greatly facilitated should a pharmaceutical cystinotic mouse would be a necessary pre- human patients with cystinosis (J. G.
the possibility of improved diagnosis for the REFERENCES
Haycock GB, Al-Dahan J, Mak RHK, Chantler C. Effect of Manz F, Gretz N. Cystinosis in the Federal Republic of Ger- indomethacin on clinical progress and renal function in cysti- many. Coordination and Analysis of the data. J Inher Metab nosis. Arch Dis Child 1982;57:934–9.
Gahl WA, Bernardini I, Dalakas M, Rizzo WB, Harper GS, Ebbensen F, Mygind KI, Holck F. Infantile nephropathic Hoeg JM. Oral carnitine therapy in children with cystinosis cystinosis in Denmark. Dan Med Bull 1976;23:216–22.
and renal Fanconi syndrome. J Clin Invest 1988;81:549–60.
Bois E, Feingold J, Frenay P, Briard ML. Infantile cystinosis 10. Haffner D, Wuhl E, Schaefer F, Nissel R, Tonshoff B, Mehls in France: genetics, incidence, geographic distribution. J Med O. Factors predictiveof the short- and long-term efficacy of growth hormone treatment in prepubertal children with Gahl WA, Thoene JG, Schneider JA. Cystinosis: a disorder of chronic renal failure. J Am Soc Nephrol 1998;9:1899–907.
lysosomal membrane transport. In: Scriver CR, Beaudet AL, 11. Wilson DP, Jelley D, Stratton R, Coldwell JG. Nephropathic Sly WS, Valle D, Vogelstein B (editors). The metabolic and cystinosis: improved linear growth after treatment with molecular basis of inherited disease (8th ed). New York: recombinant human growth hormone. J Paed 1989;115: Town M, Antignac C. Molecular characterization of CTNS 12. Pisoni R, Thoene J, Christtensen H. Detection and charac- deletions in nephropathic cystinosis: development of a PCR- terization of carrier mediated cationic amino acid transport in based detection assay Am J Hum Genet 1999;65:353–9.
lysomsomes of normal and cystinotic fibroblasts. Role in Forestier L, Jean G, Attard M, Cherqui S, Lewis C, van’t therapeutic cystine removal? J Biol Chem 1995;260:4791–8.
Hoff W, et al. Oral carnitine therapy in children with cysti- 13. Owen B, Rowley G, Sharkey IM, Coulthard MG. Develop- nosis and renal Fanconi syndrome. J Clin Invest 1988; ment of cysteamine hydrochloride pellets for cystinotic infants. Eur Hosp Pharm 1997;3:136–42.
Betend B, Pugeaut R, David L, Hermier M, Francois R. Pae- 14. Cardwell WA, Cairns D, Anderson RJ. Synthesis and evalua- diatric cystinosis: an experience with indomethacin therapy.
tion of cysteamine analogues. J Pharm Pharmacol 1997;

Source: http://www.cystinosis.org.uk/wp-content/uploads/2010/01/pj_20021026_cystinosis.pdf