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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 溶酶体储存疾病是一组异质性疾病，其特征是几种酶中的一种存在遗传缺陷，这些酶是分解身体许多器官中的代谢物所必需的。在某些情况下，酶缺乏会对中枢神经系统(CNS)产生深远的影响，导致进行性神经退化和过早死亡。目前，有几种治疗方法可以治疗这些疾病，但还没有可以延缓或防止中枢神经系统神经变性的治疗方法。因此，该项目的总体目标是利用来自骨髓的干细胞，称为间充质干细胞(MSCs)，作为细胞载体来重建大脑中缺乏酶活性的方法，以延缓和/或防止神经退化。本研究将骨髓间充质干细胞直接注射到非人类灵长类动物(猕猴)的中枢神经系统内，并对其在脑内的整体植入水平和解剖分布进行了量化。然后将这些数据与对动物健康、发育、行为和运动技能的影响相关联，以评估整体方法的安全性。此外，由于在大多数情况下，骨髓间充质干细胞来自无关的捐赠者，每个移植受者的免疫状态也将受到密切监测，以寻找移植细胞的排斥迹象。一旦确定了这种方法的安全性，MSCs就会被移植到患有Krabbe病的婴儿猕猴体内，Krabbe病是一种影响神经系统的蓄积性疾病，并评估了它们对疾病进展的影响。通过使用相关的大型动物模型，从这些研究中获得的数据将有助于开发更有效的疗法来治疗患有溶酶体储存疾病的人类婴儿，这些疾病涉及中枢神经系统。

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 a heterogeneous group of disorders characterized by a genetic deficiency in one of several enzymes that are necessary for the breakdown of metabolites in many organs of the body. In some cases the enzyme deficiency has a profound affect on the central nervous system (CNS), leading to progressive neurodegeneration and premature death. Currently, several treatments are available to manage these diseases but no treatments exist that can delay or prevent neurodegeneration in the CNS. Therefore, the overall goal of this project is to exploit stem cells derived from bone marrow, referred to as mesenchymal stem cells (MSCs), as cellular vectors to reconstitute deficient enzyme activity in the brain as a means to delay and/or prevent neurodegeneration. Herein, MSCs are injected directly into the CNS of non-human primate (Rhesus macaques) infants and their overall engraftment levels and anatomic distribution in brain are quantified. These data are then correlated with effects on animal health, development, behavior, and motor skills to evaluate the safety of the overall approach. Additionally, since in most cases the MSCs are derived from an unrelated donor, the immune status of each transplant recipient will also be closely monitored to look for signs of rejection of the transplanted cells. Once the safety of the approach is established, the MSCs are transplanted into infant macaques afflicted with Krabbe disease, a form of storage disease that effects the nervous system, and their effect on disease progression is evaluated. By employing a relevant large animal model, data obtained from these studies will aide in developing more efficacious therapies for treating human infants afflicted with lysosomal storage disease that involved the CNS.