Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
Edward H
EH
Schuchman
Yi
Y
Ge
Alon
A
Lai
Yury
Y
Borisov
Meghan
M
Faillace
Efrat
E
Eliyahu
Xingxuan
X
He
James
J
Iatridis
Helen
H
Vlassara
Gary
G
Striker
Calogera M
CM
Simonaro
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016916:Joint Deformities, Acquired / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009087:Mucopolysaccharidosis VI / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D014409:Tumor Necrosis Factor-alpha; D010426:Pentosan Sulfuric Polyester; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C518696:Adamts5 protein, rat