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Catherine McKeon, Ph.D.
Senior Advisor for Genetic Research
National Institute of Diabetes
and Digestive and Kidney Diseases

The National Institutes of Health (NIH) under the Department of Health and Human Services (DHHS) is the major funder of scientific research in the United States. The NIH funds studies in many aspects of medical research at universities and research organizations across the country. Several components of the NIH support research on MSUD including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Child Health and Human Development. NIH-funded researchers have contributed to our knowledge of MSUD by identifying the enzyme defect in the branch-chain alpha-ketoacid dehydrogenase complex (BCKD) and the underlying genetic defects in MSUD. These discoveries have led to the development of a test for MSUD that can detect the disease in newborns so that dietary treatment can begin prior to the development of serious consequences. Although some states have adopted this newborn screening test, many have not. The DHHS Secretary’s Advisory Committee on Genetics, Health and Society has recommended that all states include MSUD in their newborn screening programs.

Dietary treatment, especially when instituted from birth, has dramatically improved the quality of life for patients with MSUD, but it is far from a cure. Researchers are looking at many different ways to improve therapies for patients with MSUD. Some of this research is focused on gene therapy and liver transplantation, therapies that might be useful for many diseases. Others are more specific to MSUD itself.

Many NIDDK-funded Investigators are working to try to improve gene delivery to the liver. This approach, once perfected, should be applicable for delivering the genes for many genetic conditions including the genes responsible for MSUD. Two vector systems are currently showing promise in animal models. One vector is based on a modification of an adenovirus vector. This vector, called a helper-dependent adenovirus, has all of the adenovirus genes removed. In an animal model, genes delivered with this vector were expressed for over a year. Another promising vector is a new form of adenovirus associated virus, AAV type 8. This form of AAV has been shown to be more efficient in transducing liver cells than other forms of AAV. Both of these vector systems are undergoing toxicity testing in preparation for trials in patients.

Several recent advances have expanded our knowledge on MSUD and may provide new avenues for treatments. There are 6 genes that encode subunits of the BCKD complex. By studying the mutations that cause MSUD, investigators hope to gain a better understanding of the interactions between these proteins. Recently, NIDDKsupported investigator Dr. David Chuang at the University of Texas investigated the mutations that cause MSUD in an Israeli population that has a relatively high incidence of MSUD. They were able to define the mutations in 8 patients. Although some mutations totally disrupt the function of the protein, others prevent proper folding and assembly of this enzyme complex. In cases where the protein is made but not properly folded, it may be possible to increase the amount of functioning protein. In these patients, a mutation was described that could be treated with high doses of the cofactor thiamine, which helps the complex to assemble and become active, reducing the severity of the disease. By comparing these patients with other patients with the thiamine-responsive form of the disease, Dr. Chuang has determined that the presence of one E2 expressing allele is diagnostic for the thiamin-responsive form of the disease. This discovery identifies one group that can benefit from a method to increase protein folding and assembly. Other molecules that increase folding are currently being studied as potential treatments.

Another possible lead for treating MSUD was found by an NIDDK-supported investigator, Dr. Brendan Lee, at Baylor College of Medicine when studying another rare disease. Dr. Lee was studying the effect of the drug, Buphenyl on the metabolism of patients with urea cycle defects. Dr. Lee found that this drug therapy reduced serum branched chain amino acids in these patients. Since the branch chain amino acids accumulate in MSUD, this drug may also be useful in the treatment of MSUD. Dr. Lee is beginning a clinical trial with this drug for MSUD. Anyone interested in more information regarding this project can contact Sandy Bulcher.

These are two specific examples of research that could lead to improved treatments for MSUD. You can find more details on these studies in the references below:

  • Structural and Biochemical Basis for Novel Mutations in Homozygous Israeli Maple Syrup Urine Disease Patients. JL Chuang, RM Wynn, CC Moss, J Song, J Li, N Awad, H Mandel and DT Chuang. The Journal of Biological Chemistry 279:17792 (2004)
  • Effect of alternative pathway therapy on branch chain amino acid metabolism in urea cycle disorder patients. F Scaglia, S Carter, WE OBrien and B Lee. Molecular Genetics and Metabolism 81: S70 (2004)

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