30 Jul 2013, BioSpectrum Bureau , BioSpectrum
Singapore: A team led by researchers at the National Institutes of Health (NIH), using genetically engineered mice created for their studies, has identified a set of biomarkers for rare disease called methylmalonic acidemia (MMA) leading to kidney damage and demonstrated that antioxidant therapy protected kidney function in the mice.
Researchers at the National Human Genome Research Institute (NHGRI), part of NIH, validated the same biomarkers in 46 patients with MMA seen at the NIH Clinical Center. The biomarkers offer new tools for monitoring disease progression and the effects of therapies, both of which will be valuable in the researchers' design of clinical trials for this disease.
MMA can have several different causes, all involving loss of function of a metabolic pathway that moderates levels of an organic compound called methylmalonic acid. Affected children are unable to properly metabolize certain amino acids consumed in their diet, which damages a number of organs, most notably the kidneys.
"Metabolic disorders like MMA are extremely difficult to manage because they perturb the delicate balance of chemicals that our bodies need to sustain health," said Dr Daniel Kastner, NHGRI scientific director. "Given that every newborn in the United States is screened for a number of inherited metabolic disorders, including MMA, there is a critical need for better understanding of the disease mechanisms and therapies to treat them."
MMA is the most common organic acid disorder and invariably impairs kidney function, which can lead to kidney failure. The most common therapy is a restrictive diet, but doctors must resort to dialysis or kidney transplantation when the disease progresses. MMA patients also suffer from severe metabolic instability, failure to thrive, intellectual and physical disabilities, pancreatitis, anemia, seizures, vision loss and strokes.
The researchers chose one of the biomarkers, called lipocalin-2, to test how it correlated with kidney function in 46 MMA patients. Plasma levels of this biomarker rose with kidney deterioration in patients with MMA, and may serve as a valuable indicator of MMA kidney disease progression in the clinic.
"The detection of biomarkers through microarray technology is immensely helpful in pointing to downstream pathways affected by the defective MUT activity," said Dr Irini Manoli, lead author and a physician scientist and staff clinician in NHGRI's Genetics and Molecular Biology Branch. "The biomarkers provide new plasma or serum tests to follow disease progression in our patients."
Having discovered these important biomarkers of kidney function, the authors turned to kidney physiology experts on their team to explore the structural changes that occur in MMA disease. They analyzed the rate at which the kidneys filter waste from the blood. Co-author and renal physiology expert Dr. Jurgen Schnermann, and members of his laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), also part of NIH, demonstrated the early and significant decrease in this rate in MMA mice.