Journal Article

Pentosan Polysulfate: A Novel Therapy for the Mucopolysaccharidoses

Schuchman, Edward H., Vlassara, Helen, Striker, Gary, Simonaro, Calogera M., Ge, Yi, He, Xingxuan, Lai, Alon, Borisov, Yury, Faillace, Meghan, Iatridis, James, Eliyahu, Efrat

2013

Overview

Pentosan 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. Treatment 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. Based 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ADAM Proteins - genetics / ADAM Proteins - metabolism / ADAMTS5 Protein / Animal models / Animal tissues / Animals / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Antibodies / Arthritis / Bioaccumulation / Biology / Biomarkers - metabolism / Biomechanics / Bone and Bones - drug effects / Bone and Bones - metabolism / Bone and Bones - pathology / Bone Density - drug effects / Cancellous bone / Care and treatment / Cartilage / Chemokine CCL3 - genetics / Chemokine CCL3 - metabolism / Chemokine CCL5 - genetics / Chemokine CCL5 - metabolism / Chondrocytes / Chondrocytes - drug effects / Chondrocytes - metabolism / Chondrocytes - pathology / Computed tomography / Cortical bone / Degeneration / Disease / Drug dosages / Drug therapy / Drugs / Enzymes / Eye / Female / Femur / Fibroblasts / Gene expression / Gene Expression - drug effects / Geriatrics / Glycosaminoglycans / Grooming / Health aspects / Health services / Immunotherapy / Inflammation / Joint Deformities, Acquired - drug therapy / Joint Deformities, Acquired - metabolism / Joint Deformities, Acquired - pathology / Markers / Medicine / Mucopolysaccharidoses / Mucopolysaccharidosis / Mucopolysaccharidosis VI - drug therapy / Mucopolysaccharidosis VI - metabolism / Mucopolysaccharidosis VI - pathology / Orthopedics / Palliative care / Pentosan polysulfate / Pentosan Sulfuric Polyester - pharmacology / Prenatal development / RANTES / Rats / Rodents / Secretions / Spines / Teeth / Therapy / Tissue inhibitor of metalloproteinase 1 / Transplants & implants / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-α / Vertebrae / Xylans