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 treatment are described

ephropathic cystinosis is a rare The disease is caused by a defect in the cystinosis, or may be unrelated to the condi- autosomal recessive disease lysosomal transport mechanism for cystine tion. The daily drug regimen of a typical with an annual incidence rate and results from mutations in CTNS (cys- cystinotic patient is presented in Panel 3. in Europe of between one in tine transport nephrotic syndrome), the This patient is post-transplant and is receiv- N115,000 and one in 179,000 live births.1,2 gene on chromosome 17 which codes for ing, in addition to cysteamine and carnitine, There are approximately 200 patients in the the cystine transport protein, cystinosin.5,6 treatment for epilepsy, diabetes and United Kingdom. The disease manifests A number of mutations have been described, hypothyroidism. 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- present in lysosomes, bone marrow aspi- been described in all major ethnic groups). gon). This compound acts to lower intra- rates, leukocytes, cornea and conjunctiva. cellular levels of cysteine by forming a The disease is characterised by poor growth, cysteamine-cysteine mixed disulphide within CURRENT TREATMENT renal Fanconi syndrome (impairment in 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 organs (see Panel 1). the effects of Fanconi syndrome, as well as There are major problems, however, Cystinosis is fatal if not treated and death corneal and renal transplant. Indomethacin with administration of cysteamine. The 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 and water retaining action.7,8 In some smell and irritates the gastrointestinal tract, rate of renal failure. However glomerular patients, carnitine is used to combat the leading to nausea and vomiting following damage present at the time of diagnosis 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 halitosis and body odour. Furthermore, The condition has been recently reviewed.3,4 muscle tissue9 and human growth hormone some patients exhibit more serious side is used to promote short- and long-term effects, such as neutropenia. As a result of growth in short children with chronic renal these problems, patient compliance is poor. failure.10 Growth hormone may also help Panel 1. Symptoms of improve growth velocity in children with FUTURE TREATMENTS nephropathic cystinosis11 (Panel 2). cystinosis The number of medicines taken daily by In an attempt to overcome the problems a cystinosis patient is often considerable, associated with administration of cyste- l Renal Fanconi syndrome especially when serious medical conditions amine, two recent projects have been estab- (impairment in proximal tubular such as epilepsy or diabetes, are present. lished at the University of Sunderland. A function) These conditions may arise subsequent to team led by Professor Geoff Rowley has l Polyuria (excessive urination) attempted the formulation of cysteamine l Polydipsia (excessive thirst) into a sustained release form.13 This, it is l Hypokalaemia (low levels K+) hoped, will minimise the gastric irritation l Hypophosphataemia (low levels Panel 2. Treatments experienced by patients taking large oral 3- PO4 ) doses of cysteamine and improve patient l Crystals of cystine present in for cystinosis compliance. A second, more radical lysosomes, bone marrow aspirates, approach, pioneered in our own laborato- leukocytes, cornea and conjunctiva l Administration of electrolytes, l Photophobia, headaches, burning or glucose etc, to address imbalance itching of eyes l Regular renal dialysis Dr Cairns and Dr Anderson are senior lecturers l Growth retardation, rickets, muscle l Renal transplant (requires in the Institute of Pharmacy, Chemistry and myopathy immunosuppressant therapy) Biomedical Sciences, University of Sunderland. l Central nervous system involve- l Eye drops, corneal transplant Dr Coulthard is a paediatric nephrologist, Royal ment, hypothyroidism l Indomethacin Victoria Infirmary, Newcastle-upon-Tyne, and Mr Terry is founder and adviser, Cystinosis l Hepatic and gastrointestinal l Carnitine Foundation UK. Correspondence to Dr Cairns l complications Growth hormone (e-mail [email protected])

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Panel 3. Daily drug regimen for a typical patient with cystinosis

Cysteamine bitartrate 750mg tid Sodium valproate 500mg bd Glibenclamide 2.5mg od Thyroxine 50 mg tid alternate days Clobazam 10mg bd Prednisolone 15mg od alternate days Ciclosporin 0.9ml bd L-Carnitine 500mg tid BreathAssure 4 caps tid

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 and hypothyroidism ries, has concentrated on the design and into cells) and improved pharmacokinet- synthesis of prodrug derivatives of cys- ic and pharmacodynamic profiles. teamine. Prodrugs often exhibit desirable We have already synthesised a small num- improvements over the parent drug, such as ber of cysteamine prodrugs and determined disease (through mutation detection) and increased lipophilicity (which aids uptake their general cytotoxicity in cultures of expo- work is under way in Europe and in the nentially growing Chinese hamster ovary United States to establish a knock-out 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 Cystinosis Foundation UK ability to deplete cystine in cultured cystinotic occurring animal model. A “mouse with w w w.cystinosis.org.uk 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 Cystinosis Foundation USA drug approach for cystinosis will target cyste- potentially exciting use for these animals is w w w.cystinosis.com amine to those cells that need it most, as a target for gene therapy. Once the mouse drastically reduce side effects and eliminate model has been developed, work can begin Cystinosis Research Network the need for repeated daily dosing. The devel- on correcting the defect using a proper w w w .cystinosis.org opment of prodrugs for cystinosis would be functioning CTNS gene. Successful genetic greatly facilitated should a pharmaceutical correction of kidney dysfunction in the Children Living with Inherited company decide to adopt this orphan cystinotic mouse would be a necessary pre- Metabolic Diseases (CLIMB) disease. amble to developing gene therapy for w w w.climb.org.uk The discovery of the CTNS gene offers human patients with cystinosis (J. G. the possibility of improved diagnosis for the Thoene, personal communication).

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