There's a heartbreaking gap between understanding the underlying causes of cystinosis and finding an effective therapy, reports Cormac Sheridan
Developing novel therapies for the rare genetic condition, cystinosis, remains a tough challenge, according to Dr Bill Gahl, one of the world's leading authorities on the subject. Gahl visited Ireland late last month to share his clinical expertise with the patient advocacy group, Cystinosis Foundation Ireland (CFI), and with the wider medical community here.
Cystinosis, which occurs at a frequency of about one in 200,000 live births, illustrates quite starkly the heartbreaking gap between understanding the mechanism underlying a particular disease and finding a truly effective therapy. It also highlights the particular vulnerability of people with rare diseases. In Ireland, there are just eight people, distributed across five families, who are living with cystinosis.
The biochemistry of the condition was worked out in the late 1960s. It is characterised by an accumulation of the amino acid cystine in the lysosomes of patients' cells.
The lysosome, an organelle or compartment within the cell, is the cell's molecular recycling centre. It breaks down old cellular components and foreign material, such as bacterial cells, into their molecular constituents and exports them back out into the cell's cytoplasm for reuse.
The disease's associated molecular biology was unravelled in 1998, when researchers based in France and the UK identified the gene CTNS, which encodes a protein, cystinosin, responsible for transporting cystine across the lysosomal membrane. Mutations in this gene are responsible for cystinosis.
Cystine accumulation in the lysosome leads to a wide array of severe problems, including kidney failure, growth deficits, swallowing difficulties, sensitivity to light due to the formation of cystine crystals in the eye and, eventually, blindness. If untreated, patients generally die of kidney failure at 10 years.
Kidney transplants are now a common intervention. Gahl, who is intramural clinical director at the National Human Genome Research Institute at the US National Institutes of Health, also helped to establish the efficacy of a drug called cysteamine as a treatment for cystinosis during the 1970s.
However, cysteamine (also known by its brand name Cystagon) is a difficult drug to take. It needs to be administered at strict six-hour intervals, it causes severe nausea, it has a bitter taste and it also creates an unpleasant smell, leading to significant compliance problems once cystinosis patients reach adolescence.
Although it has provided increased life expectancy to cystinosis patients, it is by no means a cure.
CFI, which has raised some €150,000 since its launch in November 2003, has sponsored researcher Dr Donald Cairns, associate head of pharmacy at Robert Gordon University (RCU) in Aberdeen, Scotland, who is attempting to develop a "prodrug" formulation of cysteamine. This would hopefully render it odourless and tasteless while passing through the gastro-intestinal tract.
Another group in the US is studying the drug's absorption properties in the gut in order to develop a delayed release version, which would allow for a reduction in dosing frequency. "That would be an improvement," Gahl says.
Gene therapy, however, is not a realistic option in the short term. "That's a real tough one. This is a disease that affects all different cell types," he says.
Meanwhile, outside of Europe and the USA, which have a combined 1,100 cystinosis patients, access to the current drug remains an outstanding problem. "There are 30 patients in Brazil who cannot get cysteamine," Gahl says.
• Cystinosis Foundation Ireland has a team running in the Women's Mini-Marathon on June 6th and is still looking for additional runners. www.ireland.cystinosis.com