Mucopolysaccharidosis I (MPS I) and MPS V Mucopolysaccharidosis I (MPS I) and MPS VII are lysosomal storage diseases in which glycosaminoglycans (GAG) accumulate due to deficient activity in a-Liduronidase and b-glucuronidase, respectively. This results in multisysten, which are very important for their structural integrity. We hypothesize that upregulation of proteases that degrade these proteins is a common pathophysiological pathway to disease in aorta and spine. Aortas undergo elastin fragmentation and progressive dilatation, which can result in cardiovascular insufficiency and require surgery. We have previously shown that aortic disease is associated with upregulation of elastases of the cathepsin and matrix metalloproteinase (MMP) families in mouse models of MPS I and MPS VII. A second site that is difficult to treat in MPS is the cervical spine, which can require surgery for stabilization. Radiographs demonstrate that vertebrae have destructive changes, and our preliminary data demonstrates that cathepsins are upregulated in the annulus fibrosus of the intervertebral disc and in articular cartilage.
Aim I of this project will further evaluate the pathogenesis of disease in the cervical spine of MPS VII dogs, which will involve structural studies and histopathology of the spine. In addition, the expression of genes involved in synthesis, assembly, or destruction of collagen and elastin will be evaluated in the intervertebral disc and the endplate cartilage of the vertebrae in MPS VII dogs.
The second aim of this project will attempt to determine the role of specific proteases in aorta in mice. Both cathepsin S and MMP-12 were markedly upregulated in the aorta of MPS I and MPS VII mice and dogs. MPS VII mice will be crossed with cathepsin S-deficient or MMP-12-deficient mice, and the effect upon aortic dilatation and elastin fragmentation will be evaluated. If a specific gene appears to play a major role in elastin fragmentation, subsequent studies in the future would test the effect of drugs that can inhibit these proteases. These studies may demonstrate that the development of disease in the aorta and the cervical spine in MPS is due to a common mechanism, and may identify a therapy for these difficult-to-treat sites.

Public Health Relevance

Mucopolysaccharidosis I (MPS I) and MPS VII are lysosomal storage diseases that result in the accumulation of glycosaminoglycans in lysosomes of organs throughout the body. They result in many clinical symptoms, which include but are not limited to the aorta and spine. Although treatments for MPS such as hematopoietic stem cell transplantation (similar to bone marrow transplantation) or enzyme replacement therapy are effective in some sites, these therapies do not prevent disease in the aorta and spine. Similarly, although gene therapy has been effective at many sites in animal models of MPS, the aorta and the spine have been difficult to treat. The goal of this project is to obtain a better understanding of how the accumulation of glycosaminoglycans in MPS results in abnormalities of the aorta and spine. It is likely that upregulation of proteases that damage the aorta and the spine is important for the development of disease in these sites. Identification of specific proteases that damage aorta and spine might result in identification of drugs that can prevent them from damaging tissues. The results of this study may improve the longevity and quality of life in patients with MPS.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD061879-01A1
Application #
7729874
Study Section
Special Emphasis Panel (ZHD1-MRG-C (09))
Program Officer
Oster-Granite, Mary Lou
Project Start
2009-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$396,581
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Xing, Elizabeth M; Wu, Susan; Ponder, Katherine P (2015) The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice. Mol Genet Metab 114:209-16
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Bigg, Paul W; Sleeper, Meg M; O'Donnell, Patricia A et al. (2013) The effect of neonatal gene therapy with a gamma retroviral vector on cardiac valve disease in mucopolysaccharidosis VII dogs after a decade. Mol Genet Metab 110:311-8
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Smith, Lachlan J; Martin, John T; O'Donnell, Patricia et al. (2012) Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs. Mol Genet Metab 107:145-52
Ponder, Katherine P; O'Malley, Thomas M; Wang, Ping et al. (2012) Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats. Mol Ther 20:898-907

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