Simonaro Calogera M, Tomatsu Shunji, Sikora Tracy, Kubaski Francyne, Frohbergh Michael, Guevara Johana M, Wang Raymond Y, Vera Moin, Kang Jennifer L, Smith Lachlan J, Schuchman Edward H, Haskins Mark E
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
Skeletal Dysplasia Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States of America.
PLoS One. 2016 Apr 11;11(4):e0153136. doi: 10.1371/journal.pone.0153136. eCollection 2016.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
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.
我们之前在黏多糖贮积症（MPS）VI型大鼠模型中证明了戊聚糖多硫酸酯（PPS）的治疗益处。研究显示其具有减轻炎症、减少糖胺聚糖（GAG）蓄积以及改善骨骼表型的作用。在此，我们评估PPS在不同类型MPS（MPS I型犬）的大型动物模型中的长期安全性和治疗效果。我们将重点放在动脉表型上，因为这是该模型最一致且临床上最显著的特征之一。
方法/主要发现：MPS I型犬分别以相当于人类剂量1.6 mg/kg的剂量每日口服或每两周皮下注射（subQ）PPS，持续17个月和12个月。在6个月时和研究结束时评估安全参数。治疗后，测定体液和组织中的细胞因子和GAG水平。还对主动脉和颈动脉进行了评估。未观察到与药物相关的肝酶、凝血因子升高或其他不良反应。在尿液和脑脊液（CSF）中发现白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α）显著降低。在尿液和组织中观察到GAG减少。在接受PPS治疗的动物的颈动脉和主动脉中，管腔开口增加，内膜中层增厚减少，同时储存空泡减少。这些结果与GAG蓄积减少、簇集素1染色减少以及弹性蛋白完整性改善相关。在接受治疗的动物的脊柱中未观察到显著变化。
PPS治疗导致MPS I型犬尿液和组织中促炎细胞因子和GAG蓄积减少，皮下注射后最为明显。皮下注射还导致脑脊液中细胞因子显著减少。两个治疗组均表现出颈动脉和主动脉炎症明显减轻、血管完整性增加以及组织病理学改善。我们得出结论，PPS可能是一种安全且有用的MPS I型治疗方法，可作为辅助治疗或作为减少炎症和GAG蓄积的单独治疗方法。
