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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 溶酶体贮积病是一组异质性疾病，其特征在于在身体的许多器官中分解代谢物所必需的几种酶之一中的遗传缺陷。 在某些情况下，酶缺乏对中枢神经系统（CNS）有深远的影响，导致进行性神经变性和过早死亡。 目前，有几种治疗方法可用于管理这些疾病，但不存在可以延迟或预防CNS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（MSC），作为细胞载体来重建大脑中缺乏的酶活性，作为延迟和/或预防神经变性的手段。 在此，将MSC直接注射到非人灵长类动物（恒河猴）婴儿的CNS中，并定量其在脑中的总体植入水平和解剖分布。 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，MSC来自无关供体，因此也将密切监测每个移植受体的免疫状态，以寻找移植细胞排斥的迹象。 一旦建立了该方法的安全性，将MSC移植到患有Krabbe病的婴儿猕猴中，Krabbe病是一种影响神经系统的储存疾病，并评估其对疾病进展的影响。 通过采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治疗方法，用于治疗患有涉及CNS的溶酶体贮积病的人类婴儿。

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.