Enzyme replacement therapies (ERTs) are available for three of the MPS, but do not significantly improve the cartilage, bone or spinal disease. Thus, treatment of these abnormalities in MPS patients represents an important unmet medical need. Pentosan polysulfate (PPS) is an FDA-approved, oral medication that has potent anti-inflammatory and clinical effects in animal models of several diseases, including osteoarthritis and intervertebral disc degeneration. It is currently approved for use in patients with interstitial cystitis, and its safety has been demonstrated through clinical testing. In this proposal PPS will be administered to MPS VI rats of various ages, including pregnant mothers, and the age-related effects on cartilage, bone and spinal disease will be evaluated by motility assays, microCT analyses of bone density and structure, histology, immunohistochemistry, biochemistry, and by biomechanical analysis of the structure and composition of bone, cartilage and spinal tissues.
Aim 1 will examine oral administration of PPS to MPS VI animals of various ages;
aim 2 will evaluate dose-related effects of oral PPS treatment;
aim 3 will compare oral PPS to subcutaneous and intramuscular treatment;
and aim 4 will evaluate the benefits of combined ERT/PPS treatment over ERT or PPS alone. PPS could represent the first oral medication for MPS, and if these experiments are successful could have a very high and immediate impact on the treatment and management of patients with these disorders.

Public Health Relevance

The MPS are a family of inherited enzyme deficiencies that result in severe and debilitating cartilage, bone and spinal disease. The only existing treatments for MPS, enzyme replacement therapy (ERT) and bone marrow transplantation, do not significantly impact these important features of the disease. ERT also requires regular intravenous infusions. PPS could therefore represent a break-through treatment for MPS because a) it is an oral therapy and b) preliminary animal model studies have indicated an important effect on MPS skeletal disease and inflammation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
Program Officer
Leschek, Ellen W
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Simonaro, Calogera M; Tomatsu, Shunji; Sikora, Tracy et al. (2016) Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs. PLoS One 11:e0153136
Frohbergh, Michael; Ge, Yi; Meng, Fanli et al. (2014) Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment. PLoS One 9:e100882
Schuchman, Edward H; Ge, Yi; Lai, Alon et al. (2013) Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses. PLoS One 8:e54459