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

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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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 TechnologyNetworks.com 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

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
Genetic Link For Rare Intestinal Cancer
Researchers recommend screening for people with family history.
Thursday, April 16, 2015
Genetics Help Predict Heart Disease Risk, Statin Benefits
Researchers found that a set of genetic variants could identify people at risk for coronary heart disease and who would benefit most from statin therapy.
Tuesday, March 24, 2015
NIH Grants Aim To Decipher The Language Of Gene Regulation
The GGR program aims to develop new ways for understanding how the genes and switches in the genome fit together as networks.
Tuesday, January 06, 2015
Study Finds Genetic Clue To Menopause-Like Condition In Young Women
NIH-funded research may also contribute to understanding normal menopause.
Thursday, December 18, 2014
Researchers Conduct Comprehensive Genomic Study of Sub-Saharan Africans
New data resource will enhance disease research and genomic diversity studies.
Friday, December 05, 2014
Chromosome Region Linked to Gigantism
Duplication of gene on X chromosome appears to cause excessive growth.
Thursday, December 04, 2014
Comprehensive Genomic Study of Sub-Saharan Africans Conducted
New data resource will enhance disease research and genomic diversity studies.
Thursday, December 04, 2014
Scientists Looking Across Human, Fly and Worm Genomes Find Shared Biology
Studies reveal powerful commonalities in biological activity and regulation among species.
Thursday, August 28, 2014
Pinpointing Genes that Protect Against Frailty
Researchers at Albert Einstein College of Medicine of Yeshiva University have been awarded a $3.3M grant from the NIH to study the role of genetics in protecting against frailty.
Thursday, August 14, 2014
Scientific News
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Marijuana Genome Unraveled
A study by Canadian researchers is providing a clearer picture of the evolutionary history and genetic organization of cannabis, a step that could have agricultural, medical and legal implications for this valuable crop.
Growing Hepatitis C in the Lab
Recent discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.
Signature of Microbiomes Linked to Schizophrenia
Studying microbiomes in throat may help identify causes and treatments of brain disorder.
Study Identifies the Off Switch for Biofilm Formation
New discovery could help prevent the formation of infectious bacterial films on hospital equipment.
Genetic Overlapping in Multiple Autoimmune Diseases May Suggest Common Therapies
CHOP genomics expert leads analysis of genetic architecture, with eye on repurposing existing drugs.
Fat in the Family?
Study could lead to therapeutics that boost metabolism.
Combo Tool
Joining molecular components expands ability to manipulate genes in specific cell types.
Team Identifies Structure of Tumor-Suppressing Protein
An international group of researchers led by Carnegie Mellon University physicists Mathias Lösche and Frank Heinrich have established the structure of an important tumor suppressing protein, PTEN.
Genes Associated With Improved Survival for Pancreatic Cancer Patients
Use of non-invasive liquid biopsies could predict in which patients the cancer could recur following surgery.
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!