Abstract
BackgroundPentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats.Methodology/Principal FindingsTreatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP-1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS-treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues.ConclusionsBased on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies.
Highlights
The mucopolysaccharidoses (MPS) comprise a group of 11 distinct lysosomal storage disorders due to inherited deficiencies of enzymes involved in glycosaminoglycan (GAG) catabolism [1,2,3], resulting in severe skin, bone and joint abnormalities, spinal cord and tracheal defects, and cardiac valve disease
Based on these findings we conclude that Pentosan polysulfate (PPS) could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies
We propose that PPS could be a safe and cost-effective therapy that might be used in combination with Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT) or other therapies for all MPS patients to improve the clinical outcomes
Summary
The mucopolysaccharidoses (MPS) comprise a group of 11 distinct lysosomal storage disorders due to inherited deficiencies of enzymes involved in glycosaminoglycan (GAG) catabolism [1,2,3], resulting in severe skin, bone and joint abnormalities, spinal cord and tracheal defects, and cardiac valve disease. Central nervous system (CNS) abnormalities occur in many MPS patients, and lifespan is invariably shortened. The first is hematopoietic stem cell transplantation (HSCT), and to date hundreds of MPS patients have received such transplants with variable success. The limited success relates to the variable engraftment efficiencies and the fact that the transplanted cells cannot reach many of the important pathological sites in MPS (e.g., articular cartilage, growth plates, brain). We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. We describe the use of PPS for the treatment of MPS type VI rats
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