Mark S. Sands, Ph.D., Professor of Medicine and Genetics
Washington University School of Medicine, Department of Internal Medicine
Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that encompass at least 50 distinct diseases. Individually, these disorders are rare but as a group they occur with a frequency of approximately 1 in 5,000 live births, making them one of the most common inherited childhood diseases.
"Although we and others have developed a number of relatively efficacious therapies, none of them completely correct the spectrum of clinical signs associated with these diseases. The only way to improve on the existing therapies is to determine the underlying mechanisms of disease. The metabolomics data have provided insights into the fundamental mechanisms of the disease and has allowed us to explore new directions with our research.”
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Mark Sands, Washington University
These diseases usually result from a deficiency in one of the many acid hydrolases localized within the lysosome. In the absence of one of these catabolic enzymes, the substrates for that enzyme accumulate to high levels within the lysosome leading to the hallmark of these diseases, lysosomal distention. Since most lysosomal enzymes are ubiquitously expressed, their absence affects most cell types and consequently results in a broad spectrum of clinical signs. These can include organomegally, skeletal dysplasia, auditory deficits, retinal degeneration, cardiac insufficiency and cognitive impairment.
About the Study
Sands’ team recently discovered that mice with various forms of LSD have a profound adipose storage deficiency. Since the normal recycling of macromolecules through lysosomal degradation is impaired in these diseases, they hypothesized that animals with these disorders are in a state of nutritional stress similar to starvation.
This is a novel way of viewing LSDs since they are typically considered diseases of excess (lysosomal storage) rather than deficiency. To support this hypothesis, Metabolon and the team at Washington University performed a metabolomics screen on normal mice and mice with mucopolysaccharidosis type I (MPSI) and discovered a number of differences that are consistent with starvation. Since this study, the team has placed MPSI mice on a high fat, simple sugar diet and showed that many of the differences detected in the initial metabolomics screen, although not completely normalized, are less pronounced and approach normal values.
A future goal of Sands’ lab is to develop effective therapies for this class of disease. For example, results from a pre-clinical experiment using a human immunodeficiency virus (HIV)-based gene transfer vector in hematopoietic stem cells from an MPS VII patient were encouraging and could form the basis of a future clinical trial. The team hopes that an increased understanding of the disease process along with improved gene transfer techniques will allow for the development of more effective treatments for this class of inherited metabolic disease. Effective treatments will require very early detection in order to allow therapies to be applied before the devastating developmental problems of these diseases take hold. Genetic screening is impractical due to the many potential lesions, but small molecule biomarkers may be key to detecting multiple forms which express similar biochemical phenotypes.