title: Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs.
abstract: BACKGROUND
  We previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model.
  
  
  RESULTS
  MPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed.
  
  
  CONCLUSIONS
  PPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.affiliation: Skeletal Dysplasia Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States of America.
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Tracy
authors.initials: T
authors.lastname: Sikora
authors.affiliation: Skeletal Dysplasia Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States of America.
authors.forename: Francyne
authors.initials: F
authors.lastname: Kubaski
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Frohbergh
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.|Pontificia Universidad Javeriana, Bogota, Colombia.
authors.forename: Johana M
authors.initials: JM
authors.lastname: Guevara
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, United States of America.|Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States of America.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, CA, United States of America.
authors.forename: Moin
authors.initials: M
authors.lastname: Vera
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kang
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Lachlan J
authors.initials: LJ
authors.lastname: Smith
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D001808:Blood Vessels / Q000187:drug effects; D002574:Cervical Vertebrae / Q000187:drug effects; D004285:Dogs; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000378:metabolism; D010426:Pentosan Sulfuric Polyester / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012449:Safety
chemical_list: D015415:Biomarkers; D006025:Glycosaminoglycans; D010426:Pentosan Sulfuric Polyester