Modelling cystinosis with human stem cells and the therapeutic potential of aspartate

Cystinosis is a rare genetic disease that causes the amino acid cystine to accumulate in the body due to mutations in the CTNS gene. In its severest form, cystinosis causes kidney failure before the age of 10. Treatment is limited to cysteamine, a cystine-depleting drug, but this only slows the progression of the disease. The toxic effects of cystine on the kidney are not well understood, yet likely hold the key to developing new treatments. We have generated stem cells from a patient with cystinosis and used these as a limitless source of tissue to study cystinosis in the laboratory. We have discovered that cystinotic stem cells are deficient in aspartate, an amino acid vital for metabolic processes including energy (ATP) production. We hypothesise that a reduced ability to generate ATP in highly metabolic kidney cells is responsible for the progressive renal failure in cystinosis. To confirm this, we propose to use state-of-the-art gene editing technology to correct the genetic defect in cystinotic stem cells. We will then coax the diseased and 'rescued' stem cells to mature into kidney cells and measure their aspartate and ATP levels. In addition, we will test the therapeutic potential of aspartate by assessing its effects on the metabolism of cystinotic cells. This work will greatly advance our understanding of how cystinosis causes kidney damage and may lead to an aspartate based therapy to treat the disease.

Award Date
19 June 2014
Award Value
Principal Investigator
Ms Anne Marie O'Dowd
Host Institution
Cystinosis Foundation Ireland
MRCG-HRB Joint Funding Scheme