Department of Genetics, Cell Biology and Development, University Minnesota, Minneapolis, MN, United States; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, United States.
Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.
Mol Genet Metab. 2023 Apr;138(4):107539. doi: 10.1016/j.ymgme.2023.107539. Epub 2023 Feb 10.
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
黏多糖贮积症 II 型（亨特综合征，MPS II）是一种 X 连锁隐性遗传性疾病，由艾度糖-2-硫酸酯酶（IDS）缺乏引起，导致糖胺聚糖（GAG）硫酸乙酰肝素和硫酸皮肤素的积累。MPS II 的小鼠模型已在多个报告中用于研究疾病病理学，并对当前和下一代治疗方法进行临床前研究。在这里，我们报告了 MPS II 免疫缺陷小鼠模型的生成和特征，其中 CRISPR/Cas9 被用于敲除 NOD/SCID/Il2rγ（NSG）免疫缺陷背景下的一部分鼠 IDS 基因。IDS NSG 小鼠的血浆和所有分析组织中均检测不到 IDS 活性，并且在相同组织和尿液中 GAG 水平升高。组织病理学显示 NSG-MPS II 小鼠的外周和中枢神经系统中均有空泡化细胞。该模型再现了骨骼疾病表现，如颧骨弓直径增加和股骨长度减少。还观察到 NSG-MPS II 模型在空间记忆和学习方面的神经认知缺陷。我们预计这种新的免疫缺陷模型将适合涉及用于治疗 MPS II 的人细胞产物异种移植的临床前研究。
