Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, CA, USA.
Comparative Pathology Laboratory, University of California Davis, School of Veterinary Medicine, Davis, CA, USA.
Sci Rep. 2023 Oct 27;13(1):18439. doi: 10.1038/s41598-023-45178-0.
Mucopolysaccharidosis III (MPSIII, Sanfilippo syndrome) is a devastating lysosomal storage disease that primarily affects the central nervous system. MPSIIIA is caused by loss-of-function mutations in the gene coding for sulfamidase (N-sulfoglucosamine sulfohydrolase/SGSH) resulting in SGSH enzyme deficiency, a buildup of heparin sulfate and subsequent neurodegeneration. There is currently no cure or disease modifying treatment for MPSIIIA. A mouse model for MPSIIIA was characterized in 1999 and later backcrossed onto the C57BL/6 background. In the present study, a novel immune deficient MPSIIIA mouse model (MPSIIIA-TKO) was created by backcrossing the immune competent, C57BL/6 MPSIIIA mouse to an immune deficient mouse model lacking Rag2, CD47 and Il2rg genes. The resulting mouse model has undetectable SGSH activity, exhibits histological changes consistent with MPSIIIA and lacks T cells, B cells and NK cells. This new mouse model has the potential to be extremely useful in testing human cellular therapies in an animal model as it retains the MPSIIIA disease phenotype while tolerating xenotransplantation.
黏多糖贮积症 III 型（MPSIII，Sanfilippo 综合征）是一种破坏性的溶酶体贮积病，主要影响中枢神经系统。MPSIIIA 是由于编码磺酰胺酶（N-磺基葡萄糖胺磺基水解酶/SGSH）的基因突变导致 SGSH 酶缺乏，从而导致肝素硫酸积累和随后的神经退行性变。目前，MPSIIIA 没有治愈或改善疾病的治疗方法。1999 年，人们对 MPSIIIA 的小鼠模型进行了描述，并随后回交至 C57BL/6 背景下。在本研究中，通过将免疫功能正常的 C57BL/6 MPSIIIA 小鼠回交至缺乏 Rag2、CD47 和 Il2rg 基因的免疫缺陷小鼠模型，创建了一种新型的免疫缺陷型 MPSIIIA 小鼠模型（MPSIIIA-TKO）。由此产生的小鼠模型 SGSH 活性检测不到，表现出与 MPSIIIA 一致的组织学变化，并且缺乏 T 细胞、B 细胞和 NK 细胞。由于该新型小鼠模型保留了 MPSIIIA 的疾病表型，同时耐受异种移植，因此在动物模型中测试人类细胞疗法具有很大的潜力。
