SAFETY OF MESENCHYMAL STEM CELL ADMINISTRATION TO THE CNS OF RHESUS MACAQUES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 溶酶体贮积症是一种罕见的自身免疫性遗传病，是由于溶酶体酶缺乏引起的，其中一些酶参与中枢和外周神经系统的髓鞘形成。 从骨髓中分离的非造血间充质（基质）干细胞（MSC）已显示出免疫调节特性，包括移植到MHC错配受体时相对较低的同种异体免疫原性。 在这项研究中，我们颅内注射125万异基因离体扩增的MSC到1个月大的恒河猴患有早期发病的克拉布氏病，并在6个月时重复注射。 最初的GALC水平实际上为零，并与疾病的早期发作相关。在第1次和第2次手术后10天观察到对移植的MSC的同种免疫应答，如中性粒细胞、单核细胞和淋巴细胞的数量增加。在术后30-60天内，这些数字逐渐恢复到术前值。免疫同种异体反应的模式与健康年龄匹配的恒河猴MSC受体相似。没有移植或手术相关的副作用。两次移植后均观察到疾病症状暂时改善。此外，在第二次手术后，注意到精细运动和认知有所改善。观察到的改善与整个研究期间进行的肌电图结果相关。 此外，第一次手术后3个月进行的MRI显示了一些髓鞘形成，包括后来使用靶向Y染色体的实时PCR检测发现供体男性DNA的区域。此外，对受Krabbe影响的婴儿进行的广泛的神经行为测试显示，两次手术后大运动的改善以及第二次手术后较低水平的躁动和恐惧。 该研究揭示了成体间充质干细胞在开发治疗具有神经后遗症的溶酶体贮积症方面的潜在益处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Lysosomal storage disorders are rare autoimmune genetic diseases caused by a deficiency of lysosomal enzymes some of which are involved in myelination of central and peripheral nervous system. Non-hematopoietic mesenchymal (stromal) stem cells (MSCs) isolated from bone marrow have shown immuno-modulative properties including relatively low allo-immunogenicity when transplanted into MHC-mismatching recipients. In this study we intracranially injected 1.25 million allogeneic ex-vivo expanded MSCs to a 1 month old rhesus macaque affected with early on-set Krabbe's disease and repeated the injection at 6 months. The initial GALC level was vertually zero and correlated with an early on-set of the disease. The allo-immune response to the transplanted MSCs was observed 10 days after the 1st and 2nd surgeries as increased numbers of neutrophils, monocytes, and lymphocytes. During 30-60 days post-surgery the numbers gradually returned to the pre-surgical values. The pattern of the immune allo-response was similar to that seen in healthy age-matched rhesus MSC recipients. There were no transplantation or surgery related side effects. A temporary amelioration of disease symptoms was observed after both transplantations. Additionally, after the 2nd surgery, some improvement in fine motor movement and cognition was noticed. The observed improvement correlated with results of the electro-myogram performed throughout the study. Also, MRI taken 3 months after the 1st surgery showed some myelination including areas where the donor male DNA was found later using a real-time PCR assay targeting Y-chromosome. In addition, the extensive neuro-behavior testing of the Krabbe's affected infant showed an improvement in large motor movement after both surgeries and lower levels of agitation and fearfulness after the second surgery. The study revealed potential benefits of the adult mesenchymal stem cells for developing treatment of the lysosomal storage disorders with neurological sequels.