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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 溶酶体储存障碍是一种罕见的自身免疫性遗传病，由溶酶体酶缺乏引起，其中一些与中枢和外周神经系统的髓鞘形成有关。从骨髓分离的非造血间充质干细胞(MSCs)移植到MHC不相合的受者体内后，表现出免疫调节特性，包括相对较低的同种异体免疫原性。在这项研究中，我们将125万个体外扩增的同种异体骨髓间充质干细胞注射到一只1个月大的患有早期Krabbe病的恒河猴，并在6个月时重复注射。最初的GALC水平实际上为零，并且与疾病的早期发病相关。在第1次和第2次手术后第10天观察移植的MSCs的同种异体免疫反应，发现中性粒细胞、单核细胞和淋巴细胞数量增加。术后30-60天逐渐恢复到术前水平。免疫同种异体反应的模式与年龄匹配的健康恒河猴MSC受者相似。没有发生与移植或手术相关的副作用。在两次移植后观察到疾病症状的暂时改善。此外，第二次手术后，患者的精细运动和认知能力均有改善。观察到的改善与整个研究过程中进行的肌电图结果相关。此外，在第一次手术后3个月进行的核磁共振成像显示了一些髓鞘形成，包括后来使用针对Y染色体的实时荧光聚合酶链式反应分析发现供体男性DNA的区域。此外，对Krabbe患病婴儿进行的广泛神经行为测试显示，两次手术后大运动有所改善，第二次手术后焦虑和恐惧程度降低。这项研究揭示了成人间充质干细胞在开发治疗具有神经系统后遗症的溶酶体储存障碍方面的潜在好处。

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.