Combination therapy may offer a solution for kidney failure in cystinosis

Patients suffering from the serious kidney disease nephropathic cystinosis may in the future benefit from a new combination of existing drugs. Scientists from Utrecht University have discovered an anti-cancer drug that appears to inhibit the symptoms of kidney disease. The drug may become a welcome addition to the current drug against cystinosis, which is not fully effective and has many side effects. The researchers publish their results today in the journal EMBO Molecular Medicine.

The rare metabolic disease cystinosis is a hereditary condition that causes serious health problems at a very young age. In this disease, the amino acid cystine builds up in kidneys and other organs, causing severe damage.

Current drug

Cystinosis patients are now usually prescribed the drug cysteamine. However, that drug is far from ideal. It must be taken every six hours and causes uncomfortable side effects, one them being the production of a lot of gas in the body. Another major side effect is that patients who use the drug have a bad odour. “People get sick from the drug,” said dr. Manoe Janssen, researcher at Utrecht University. “But cystinosis patients have to take it, because otherwise they will die at a young age from the disease.”

Help from a cancer drug

By combining cysteamine with another drug, it seems possible to overcome specific disease features, Janssen and colleagues discovered. In addition, the dose of cysteamine may be reduced, leading to fewer side effects. That drug, called bicalutamide, is now mainly used as an anti-cancer drug.

They tracked down the drug after evaluating which processes were affected in cystinotic kidney cells. By comparing genetically engineered cystinosis kidney cells with ‘healthy’ control cells, they determined which metabolites were different and related to disease symptoms.

They then looked through a large collection of existing drugs to find the compounds that could reduce cystinosis symptoms. Bicalutamide appeared most effective in attenuating these symptoms.

Already approved

“A major advantage of this drug is that it is already approved and marketed,” said Janssen. “If this turns out to work well, steps towards clinical application can be taken quickly. You don't have to go through the extensive drug development and approval procedures."

Reversing symptons in zebrafish is an important sign that the drug could also work in humans

Completely reversing symptoms

The researchers saw promising results when they tested the drug in zebrafish who carried a genetic defect similar to that found in cystinosis patients. The drug turned out to completely reverse the symptoms. According to Janssen, this is an important sign that the drug can also work in humans. Zebrafish might appear to be an entirely different species, but we do share many genetic structures with each other.

According to Janssen, this is an important signal that the drug can also work in humans. Zebrafish might appear to be an entirely different species, but we do share many genetic structures with each other.

Mini kidneys

In order to be able to make the jump to humans, the researchers tried the drug on human kidney cells. They used so-called kidney organoids, or mini organs, made from kidney cells. Under the right conditions in the lab, these cells, derived from the urine of patients, can faithfully mimic various processes in the kidney and respond to drugs in a very similar way to human kidney tissue. Also, in these mini kidneys, bicalutamide was shown to be effective in reversing cystinosis symptoms.

The ultimate goal is to make an impact for patients

Impact for patients

The next step is to determine whether the drug also has a long-term beneficial effect on kidneys in patients. That should eventually pave the way for a clinical trial, where researchers can monitor the actual progress patients make when they receive both drugs. Janssen: “The ultimate goal is to make an impact for patients.”

This research was party funded by a grant from the Kolff Program of the Dutch Kidney Foundation.