Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs

Abstract

BackgroundWe 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.Methodology/Principal FindingsMPS 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.ConclusionsPPS 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.

The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls

“…The etiology of increased carotid stiffness in MPS patients is unlikely to be GAG storage alone, but rather by secondary alterations of arterial parenchyma induced by storage. Arterial inflammation, proliferation of myofibroblasts and vascular smooth muscle cells, together with attenuation and fragmentation of elastin fibrils have been observed not only in human MPS, but also in animal models [21,22,23,24]. These sequelae reduce vascular compliance via mechanisms similar to those observed in atherosclerosis [25] and Marfan syndrome [26].…”

“…Since supra-normal circulating lysosomal enzymatic levels are required for normalization of aortic pathology in animal models [27,28], therapies targeting MPS cardiovascular disease must focus on maximizing enzymatic uptake in vascular intima/media, or abrogating vascular intraparenchymal inflammation, cellular proliferation, and disruption of elastin laminae. Systemic gene therapy [27] or anti-inflammatory agents [24] show promise in preclinical studies. Human therapeutic trials anticipated in the near future should consider utilizing cIMT and carotid stiffness measurements as potential markers of cardiovascular efficacy.…”

Presentation and treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome)

“…Pentosan polysulfate (PPS), an anti-inflammatory drug approved by FDA for interstitial cystitis, is currently under investigation. The exact mechanism by which PPS decreases GAG levels and stimulates chondrocyte formation remains under investigation [111]. …”

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

“…Supplementation of ERT with simvastatin, a cholesterol-lower drug with anti-inflammatory properties, from the first week of life was found to have limited additional therapeutic benefit for preventing onset of cervical disc pathology in MPS I dogs over ERT alone after 12 months [114]. Pentosan polysulfate sodium (PPS), an oral medication with anti-inflammatory properties, has shown promise for reducing inflammation driven skeletal disease in MPS animal models [200–202]. MPS VI rats administered PPS from early in life exhibited reduced inflammation in skeletal tissues including cartilage, and improvements in vertebral bone properties [201].…”

“…MPS VI rats administered PPS from early in life exhibited reduced inflammation in skeletal tissues including cartilage, and improvements in vertebral bone properties [201]. In contrast, PPS administration was found to have limited efficacy for improving vertebral bone quality, disc condition or spinal cord compression in MPS I dogs [202]. Subcutaneous administration of PPS may be more efficacious due to enhanced bioavailability [200].…”