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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。溶酶体储存疾病是一种遗传性代谢疾病，其特征是由于酶缺乏而导致体内细胞中各种有毒物质的异常积聚。到目前为止，已有50多种此类疾病在人类中被描述，这些疾病表现为一系列临床症状。其中一些疾病的特点是储存物质在神经元和/或髓鞘产生细胞中异常堆积，导致进行性神经恶化和过早死亡。目前，还没有成熟的疗法来治疗与溶酶体储存疾病相关的神经后遗症。因此，我们的研究旨在评估成人干细胞应用于中枢神经系统治疗这些并发症的安全性、可行性和有效性。具体地说，来自骨髓的成年干细胞，称为间充质干细胞(MSCs)，将使用MRI确定的立体定位坐标，单侧注射到幼年恒河猴的尾壳核中。在使用干细胞之前和之后长达一年的不同时期，每个移植受者的健康、发育、自发行为和上肢运动能力将通过一系列测试进行评估。此外，植入中枢神经系统的骨髓间充质干细胞的水平和解剖分布将使用我们开发的实时聚合酶链式反应方法进行评估。将MSC植入脑内与对健康、发育、行为和运动功能的长期影响相关联，将直接评估MSC在脑内移植的安全性和可行性。随后，MSCs将被注射到患有球形细胞白质营养不良(Krabbe病)的幼年猕猴的中枢神经系统，其植入水平和分布将直接与整个中枢神经系统中重组半乳糖苷酶mRNA的水平和酶的活性相关。此外，将使用生化和组织学方法以及行为和运动能力测试来评估对疾病进展的影响。总的来说，这些研究将产生重要的安全性和有效性数据，有助于开发基于MSC的疗法来治疗患有储存问题的人类的神经后遗症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lysosomal storage diseases are inherited metabolic disorders characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. To date, over 50 of these disorders have been described in humans, which manifest in a wide array of clinical symptoms. Some of these disorders are characterized by abnormal accumulation of storage material in neurons and/or myelin producing cells, causing progressive neurologic deterioration and premature death. Currently, there are no established therapies for treating neurological sequelae associated with lysosomal storage diseases. Therefore, our studies aim to assess the safety, feasibility and efficacy of adult stem cell administration to the CNS for treating these complications. Specifically, adult stem cells derived from bone marrow, referred to as mesenchymal stem cells (MSCs) will be injected unilaterally into the caudate putamen of infant Rhesus macaques using stereotaxic coordinates determined by MRI. Prior to and at various periods up to 1 year post-administration of stem cells the health, development, spontaneous behavior and upper limb motor performance of each transplant recipient will be evaluated using a battery of tests. Additionally, the levels and anatomical distribution of MSCs engrafted in the CNS will be evaluated using a real-time PCR assay we developed. Correlating MSC engraftment in brain with long-term affects on health, development, behavior and motor function will directly assess the safety and feasibility of intracranial MSC administration. Subsequently, MSCs will be injected into the CNS of infant macaques afflicted with globoid cell leukodystrophy (Krabbe disease) and their engraftment levels and distribution will be directly correlated with levels of reconstituted galactocerebrosidase mRNA and enzyme activity throughout the CNS. Furthermore, affects on disease progression will be evaluated using biochemical and histological methods as well as behavioral and motor performance tests. Collectively, these studies will yield important safety and efficacy data useful for developing MSC-based therapies to treat neurologic sequelae in humans afflicted with storage