A team led by researchers at the National Institutes of Health has overcome a major biological hurdle in an effort to find improved treatments for patients with a rare disease called methylmalonic acidemia (MMA). Using genetically engineered mice created for their studies, the team identified a set of biomarkers of kidney damage — a hallmark of the disorder — 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.
The discovery, reported in the Proceedings of the National Academy of Sciences, paves the way for use of antioxidant therapy in a clinical trial for patients with MMA. It also illustrates the mechanisms by which dysfunction of mitochondria — the power generators of the cell — affects kidney disease. Mitochondrial dysfunction is a factor not only in rare disorders, such as MMA, but also in a wide variety of common conditions, such as obesity, diabetes, and cancer.
MMA affects as many as one in 67,000 children born in the United States. It 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.
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.
“There are no definitive treatments for the management of patients with MMA,” said Charles Venditti, MD, PhD, senior author and investigator in the Organic Acid Research Section of NHGRI’s Genetics and Molecular Biology Branch. “This study is the culmination of collaboration with the patient community. It uses mouse modeling, coupled with innovations in genomics and biochemical analyses, to derive new insights into the causes of renal injury in MMA. Our studies have improved our understanding of the basic biology underlying MMA, created a novel animal model for testing interventions and, now, led us to the promise of a new therapy.”
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 Irini Manoli, MD, PhD, 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.” Learn more about the study.
