Grants will boost IU School of Medicine research into family of fatal genetic diseases

  • Nov. 29, 2016

INDIANAPOLIS -- Researchers at Indiana University School of Medicine have received $4.4 million to identify new treatments for a family of fatal genetic diseases.

Peter J. Roach, PhD, distinguished professor of biochemistry and molecular biology, and the IU School of Medicine team believe that their research could lead to a new therapeutic paradigm to combat glycogen storage diseases by identifying drugs that can suppress glycogen accumulation. Their work will be supported by two five-year grants from the National Institutes of Health.

Glycogen is a normal storage form of glucose found in many tissues like muscle, heart, liver and brain. In the glycogen storage diseases, including Lafora and Pompe diseases, some of the glycogen becomes abnormal due to defects in glycogen metabolism, and can cause fatal illnesses.

In Lafora disease, the first symptom seen in apparently healthy youngsters is a major epileptic episode in their early to mid-teens. This is followed by a gradual neurological deterioration and death within ten years. The cause of Lafora disease is thought to be abnormal glycogen deposits in the neurons of the brain. Currently, there is no cure or specific therapy for this fatal disease.

In Pompe disease, there is abnormal glycogen accumulation in the skeletal muscle and the heart. The severity of the disease varies with the genetic makeup of the patient. However, in the most serious cases, the patients die before their first birthday. Existing treatments include enzyme replacement therapy, but there is a clear need for improved approaches, according to the IU School of Medicine researchers.

The IU School of Medicine team has found that by decreasing glycogen accumulation in genetically modified mice, the symptoms of Lafora and Pompe diseases can be alleviated. With this premise, Dr. Roach and his colleagues, have focused their research on discovering small molecule drugs that can decrease glycogen accumulation.

As Dr. Roach explained, "These diseases are rare but nonetheless devastating not only for the patients but also their family and friends. Our group has met with Lafora families at workshops organized by their foundation, Chelsea's Hope, and it is humbling to hear of their ordeals and their faith that we can find a cure or, at least, a treatment. We sincerely hope that this new funding can help us reach that goal by developing a novel therapy."

Support for the research is provided by the National Institute of Diabetes, Digestive and Kidney Diseases by a $2.2 million award, a continuation of a longstanding grant to Dr. Roach into its 37th year, the oldest R01 grant at Indiana University. Further support comes from a larger and more collaborative grant from the National Institute of Neurological Disorders and Stroke, a $9.1 million Program Project Grant focused on curing Lafora disease, shared with principal investigator Matthew Gentry, PhD, of the University of Kentucky. Other participating sites include University of California, San Diego, University of Toronto, Institute for Research in Biomedicine, Barcelona, and the Autonomous University of Madrid.

Additional researchers on the project, all from the Department of Biochemistry and Molecular Biology, are Thomas D. Hurley, PhD, interim chair, Anna A. DePaoli-Roach, PhD, professor emerita and Steven M. Johnson, PhD, assistant professor.

Electron microscope images of normal and abnormal glycogen molecules

These electron microscopy images demonstrate how glycogen molecules (left) become structurally abnormal (right) when excessive levels of phosphate are attached due to a mutation in the lafora gene. (Source: Indiana University School of Medicine)

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Eric Schoch
Amanjit Singh