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

间充质干细胞对恒河猴中枢神经系统给药的安全性

• 批准号: 8358038
• 负责人: Donald G Phinney
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358038
• 关键词: Adult; Adverse effects; Affect; Age; Agitation; Allogenic; Area; Autoimmune Process; Biological Assay; Bone Marrow; Cognition; DNA; Disease; Enzymes; Funding; Globoid cell leukodystrophy; Grant; Hematopoietic; Hereditary Disease; Immune; Immune response; Infant; Injection of therapeutic agent; Lymphocyte; Macaca mulatta; Magnetic Resonance Imaging; Mesenchymal; Mesenchymal Stem Cells; Motor; Movement; National Center for Research Resources; Neurologic; Operative Surgical Procedures; Pattern; Peripheral Nervous System; Primates; Principal Investigator; Property; Rare Diseases; Research; Research Infrastructure; Resources; Safety; Source; Stem cells; Symptoms; Time; Transplantation; United States National Institutes of Health; Y Chromosome; behavior test; cost; immunogenicity; male; monocyte; myelination; neutrophil; response

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 溶酶体储存障碍是罕见的自身免疫性遗传疾病，由溶酶体酶缺乏引起，其中一些涉及中枢和周围神经系统的髓鞘形成。 从骨髓中分离出的非造血性间充质（基质）干细胞（MSC）已显示出免疫调节特性，包括相对较低的同种免疫原性，当时移植到MHC抗匹配受体中时。 在这项研究中，我们颅内注射了125万个同种异体外病毒，将MSC扩展到1个月大的恒河猴，受到早期现场Krabbe病的影响，并在6个月时重复了注射。 最初的GALC水平垂直为零，并与早期的疾病相关。在第1和第二次手术后10天观察到对移植的MSC的同种免疫反应，因为中性粒细胞，单核细胞和淋巴细胞的数量增加。手术后30-60天，数字逐渐返回到术前值。免疫异种反应的模式类似于健康年龄匹配的恒河生MSC接受者中的模式。没有移植或手术相关的副作用。两次移植后都观察到了疾病症状的暂时改善。此外，在第二次手术后，注意到了精细运动和认知的一些改善。观察到的改善与整个研究过程中执行的电膜的结果相关。 另外，第一次手术后3个月进行的MRI显示了一些髓鞘化，包括后来使用针对Y染色体的实时PCR分析的供体雄性DNA的区域。此外，对Krabbe影响的婴儿进行了广泛的神经行为测试，在第二次手术后的手术和降低水平和恐惧程度较低后，大型运动的运动有所改善。 该研究揭示了成年间充质干细胞的潜在益处，用于开发具有神经系统续集的溶酶体储存障碍的治疗。