Corporate Banner
Satellite Banner
Genotyping & Gene Expression
Scientific Community
Become a Member | Sign in
Home>News>This Article

Therapy May Curb Kidney Deterioration in Patients with Rare Disorder

Published: Tuesday, July 30, 2013
Last Updated: Tuesday, July 30, 2013
Bookmark and Share
Innovation in mouse model helps researchers distinguish disease mechanisms and biomarkers.

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 July 29, 2013, advance online issue of 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. 

"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 Daniel Kastner, M.D., Ph.D., 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.

"There are no definitive treatments for the management of patients with MMA," said Charles Venditti, M.D., Ph.D., 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 modelling, 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 performed the studies using mice bred to carry gene alterations that disrupt the production of the same mitochondrial enzyme that is defective in patients with MMA. These are called transgenic mice. The enzyme, called methylmalonyl-CoA mutase (MUT), is an important component of the chemical process that metabolizes organic acids, specifically methylmalonic acid. 

By measuring gene expression in the transgenic mice using DNA microarrays, researchers discovered 50 biomarkers of gene expression that each indicated declining kidney function. DNA microarrays are silicon chips with many spots to which a given molecule may bind. In this case, the DNA microarrays were used to precisely generate, with the aid of a computer program, a profile of gene expression in a kidney cell.

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, M.D., Ph.D., 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 Jurgen Schnermann, M.D., 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. 

With further studies, the researchers identified increased production of free radicals in tissues from the mice, as well as in the MMA patients. Detection of free radicals indicates chemical instability in cells, which the researchers sought to remedy with antioxidant therapy. After treating the mice with two forms of dietary antioxidants, the researchers observed that the biomarkers of kidney damage diminished and the faltering kidney filtration rate tapered off. The findings demonstrated that readily available antioxidants can significantly affect the rate of decline of kidney function in transgenic mice, which replicate the kidney disease of MMA.

"The next step will be to translate these findings to the clinic," Dr. Venditti said. "With a progressive disorder like MMA, we are hopeful that we have achieved a laboratory success that our patients will benefit from in the near future."

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Charting Genetic Variation Across the Globe
An international team of scientists has created the world’s largest catalog of human genetic differences in populations around the globe.
Tuesday, October 20, 2015
Nuclear Transport Problems Linked to ALS and FTD
NIH-supported studies point to potential new target for treating neurodegenerative diseases.
Monday, October 19, 2015
Scientists Create World’s Largest Catalog of Human Genomic Variation
An international team of scientists from the 1000 Genomes Project Consortium has created the world’s largest catalog of genomic differences among humans, providing researchers with powerful clues to help them establish why some people are susceptible to various diseases.
Thursday, October 01, 2015
Bone Risks Linked to Genetic Variants
A large-scale genomic study uncovered novel genetic variants and led researchers to an unexpected gene that affects bone density and fracture risk.
Tuesday, September 29, 2015
Genetic Adaptations to Diet and Climate
Researchers found genetic variations in the Inuit of Greenland that reflect adaptations to their specific diet and climate.
Tuesday, September 29, 2015
NIH Framework Points The Way Forward For Developing The President’s Precision Medicine Initiative
The NIH Advisory Committee to the Director has presented to NIH Director Francis S. Collins, M.D., Ph.D., a detailed design framework for building a national research participant group, called a cohort, of 1 million or more Americans to expand our knowledge and practice of precision medicine.
Monday, September 21, 2015
Beth Israel Cardiology Team Awarded $3 Million by NIH
Work will help predict outcomes in patients with heart disease.
Friday, September 18, 2015
Diet, Exercise, Smoking Habits and Genes Interact To Affect and Risk
NIH-funded study points to converging factors that drive disease-related inflammation.
Thursday, September 17, 2015
Using Genetic Sequencing to Manage Cancer in Children
A team of scientists have investigated the feasibility of incorporating clinical sequencing information into the care of young cancer patients.
Tuesday, September 15, 2015
Tell-tale Biomarker Detects Early Breast Cancer in NIH-funded Study
The study published online in the issue of Nature Communications.
Thursday, August 13, 2015
Neurons’ Broken Machinery Piles Up in ALS
NIH scientists identify a transport defect in a model of familial ALS.
Thursday, August 13, 2015
Protein Related to Long Term Traumatic Brain Injury Complications Discovered
NIH-study shows protein found at higher levels in military members who have suffered multiple TBIs.
Tuesday, August 04, 2015
NIH Joins Public-Private Partnership to Fund Research on Autism Biomarkers
Biomarkers Consortium project to improve tools for measuring and treating social impairment in children with autism.
Tuesday, July 21, 2015
House Votes in Favor of Bill Boosting NIH Funding
The US House of Representatives today overwhelmingly voted in favor of a bill that would increase funding to the NIH by about $10 billion, help speed the development of new drugs, and advance precision medicine initiatives.
Monday, July 13, 2015
Linking Targeted Cancer Drugs to Gene Abnormalities
Investigators at the NIH have announced a series of clinical trials that will study drugs or drug combinations that target specific genetic mutations.
Wednesday, June 03, 2015
Scientific News
Genetic Basis of Fatal Flu Side Effect Discovered
A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a recent study.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Ancient Viral Molecules Essential for Human Development
Genetic material from ancient viral infections is critical to human development, according to researchers at the Stanford University School of Medicine.
Measuring microRNAs in Blood to Speed Cancer Detection
A simple, ultrasensitive microRNA sensor holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
Personalized Drug Screening for Multiple Myeloma Patients
A personalized method for testing the effectiveness of drugs that treat multiple myeloma may predict quickly and more accurately the best treatments for individual patients with the bone marrow cancer.
Metabolic Profiles Distinguish Early Stage Ovarian Cancer with Unprecedented Accuracy
Studying blood serum compounds of different molecular weights has led scientists to a set of biomarkers that may enable development of a highly accurate screening test for early-stage ovarian cancer.
New Way to Force Stem Cells to Become Bone Cells
Potential therapies based on this discovery could help people heal bone injuries or set hardware, such as replacement knees and hips.
Promise of Newborn Stem Cells to Revolutionize Clinical Practice
In this article Shweta Sharma, PhD, discusses the potential of an Umbilical Cord Blood bank as an untapped source of samples for research and clinical trials.
New Anti-Malarial Drug Screening Model
University of South Florida researchers demonstrate novel chemogenomic profiling to identify drug targets for the most lethal strain of malaria.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos