Guo Ningning, DeAngelis Victor, Zhu Changzhi, Schuchman Edward H, Simonaro Calogera M
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
JIMD Rep. 2019;43:37-52. doi: 10.1007/8904_2018_96. Epub 2018 Apr 14.
Overall Goal: This study was designed to evaluate the impact of pentosan polysulfate (PPS) treatment on mice with mucopolysaccharidosis (MPS) type IIIA (Sanfilippo A syndrome; OMIM 252900). Protocol: Three groups of MPS IIIA mice were evaluated: 1-week-old mice treated with subcutaneous (subQ) PPS at 25 mg/kg once weekly for 31 weeks (group 1); 5-month-old mice treated with subQ PPS once weekly at 50 mg/kg for 12 weeks (group 2); and 5-week-old mice treated by continual intracerebroventricular (ICV) PPS infusion for 11 weeks (60 μg/kg/day). Treated MPS IIIA mice and controls were assessed by measuring plasma cytokine levels, histologic analyses of systemic organs, and analyses of various neuroinflammatory, neurodegenerative, and lysosomal disease markers in their brains. Neurobehavioral testing also was carried out. Results: As seen in other MPS animal models, subQ PPS treatment reduced plasma cytokine levels and macrophage infiltration in systemic tissues. ICV administration did not elicit these systemic effects. SubQ PPS administration also significantly impacted brain neuropathology, inflammation, and behavior. The effect of early subQ treatment was more significant than dose. Surprisingly, ICV PPS treatment had intermediate effects on most of these brain markers, perhaps due to the limited dose and/or duration of treatment. Consistent with these neuropathological findings, we also observed significant improvements in the hyperactivity/anxiety and learning behaviors of the MPS IIIA mice treated with early subQ PPS.
本研究旨在评估戊聚糖多硫酸盐（PPS）治疗对患有IIIA型黏多糖贮积症（MPS IIIA；Sanfilippo A综合征；OMIM 252900）小鼠的影响。方案：对三组MPS IIIA小鼠进行评估：1周龄小鼠，皮下注射（subQ）25mg/kg的PPS，每周一次，共31周（第1组）；5月龄小鼠，皮下注射50mg/kg的PPS，每周一次，共12周（第2组）；5周龄小鼠，通过持续脑室内（ICV）输注PPS，共11周（60μg/kg/天）。通过测量血浆细胞因子水平、对全身器官进行组织学分析以及分析其大脑中的各种神经炎症、神经退行性变和溶酶体疾病标志物，对接受治疗的MPS IIIA小鼠和对照组进行评估。还进行了神经行为测试。结果：正如在其他MPS动物模型中所见，皮下注射PPS治疗降低了血浆细胞因子水平以及全身组织中的巨噬细胞浸润。脑室内给药未引发这些全身效应。皮下注射PPS给药也显著影响了脑部神经病理学、炎症和行为。早期皮下注射治疗的效果比剂量更显著。令人惊讶的是，脑室内PPS治疗对大多数这些脑标志物有中等程度的影响，这可能是由于治疗剂量和/或持续时间有限。与这些神经病理学发现一致，我们还观察到早期皮下注射PPS治疗的MPS IIIA小鼠的多动/焦虑和学习行为有显著改善。
