Efficient engraftment of genetically modified cells is necessary to ameliorate central nervous system involvement of murine model of mucopolysaccharidosis type II by hematopoietic stem cell targeted gene therapy
Efficient engraftment of genetically modified cells is necessary to ameliorate central nervous system involvement of murine model of mucopolysaccharidosis type II by hematopoietic stem cell targeted gene therapy
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DOI：
10.1016/j.ymgme.2020.06.007
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发表时间：
2020-08-01
影响因子：
3.8
通讯作者：
Ohashi, Toya
中科院分区：
文献类型：
--
作者：
Miwa, Saori;Watabe, Ayako M.;Ohashi, Toya
粘多糖样沉积症II型（MPS II）是一种溶酶体贮积病（LSD），由分解代谢糖胺聚糖（GAG）的艾杜糖醛酸-2-硫酸酯酶（IDS）缺乏引起。GAG在体细胞中的异常积累导致包括中枢神经系统（CNS）疾病在内的各种表现。酶替代疗法（ERT）和造血干细胞移植（HSCT）是MPS II目前可用的疗法，但这两种疗法均未能改善CNS表现。我们以前表明，造血干细胞靶向基因治疗（HSC-GT）与致死辐射改善CNS参与的MPS II缺乏IDS的基因编码的小鼠模型。然而，强预处理，伴随致死性照射，会导致高发病率和死亡率。因此，我们测试了低剂量辐射或低剂量辐射加抗c-kit单克隆抗体（ACK 2）的温和预处理程序，以评估HSC-GT后MPS II小鼠的CNS效应。所有HSC-GT组的小鼠均显示出超生理水平的IDS酶活性，外周器官中异常积累的GAG显著减少至野生型小鼠水平。然而，只有用致死性辐射处理的小鼠表现出显着的认知功能改善以及IDS升高和GAG减少在brain.These结果表明，HSC-GT的基因修饰细胞的有效植入需要强的预处理，以改善MPS II的情况下CNS参与。
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease (LSD) caused by a deficiency of the iduronate-2-sulfatase (IDS) that catabolizes glycosaminoglycans (GAGs). Abnormal accumulations of GAGs in somatic cells lead to various manifestations including central nervous system (CNS) disease. Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are the currently available therapy for MPS II, but both therapies fail to improve CNS manifestations. We previously showed that hematopoietic stem cell targeted gene therapy (HSC-GT) with lethal irradiation improved CNS involvement in a murine model of MPS II which lacks the gene coding for IDS. However, the strong preconditioning, with lethal irradiation, would cause a high rate of morbidity and mortality. Therefore, we tested milder preconditioning procedures with either low dose irradiation or low dose irradiation plus an anti c-kit monoclonal antibody (ACK2) to assess CNS effects in mice with MPS II after HSC-GT. Mice from all the HSC-GT groups displayed super-physiological levels of IDS enzyme activity and robust reduction of abnormally accumulated GAGs to the wild type mice levels in peripheral organs. However, only the mice treated with lethal irradiation showed significant cognitive function improvement as well as IDS elevation and GAG reduction in the brain.These results suggest that an efficient engraftment of genetically modified cells for HSC-GT requires strong preconditioning to ameliorate CNS involvement in cases with MPS II.