Modulation of spinal neurodegenerative diseases in swine by stem cell grafting

通过干细胞移植调节猪脊柱神经退行性疾病

基本信息

批准号：
9098821
负责人：
MARTIN MARSALA
金额：
$ 51.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098821
关键词：
Adult Allogenic Animal Model Animals Antibodies Autopsy Biological Assay Cell Line Cell Survival Cell Transplantation Cells Clinic Contusions Data Set Derivation procedure Detection Development Disease Engraftment Family suidae Fetal Tissues Fetus Fibroblasts Fingerprint Fluorescence Generations Genes Genetic Goals Graft Rejection Graft Survival HIV-1 Health Human Immunofluorescence Immunologic Immunosuppression Inbreeding Injury Isogeneic graft Label Lead Life Lumbar spinal cord structure Maintenance Miniature Swine Mixed Lymphocyte Culture Test Modeling Monitor Mononuclear Nervous System Physiology Neurodegenerative Disorders Neuroglia Neurons Nuclear Pore Complex Paraplegia Phenotype Population Pre-Clinical Model Property Protocols documentation Recovery Regimen Retroviridae Sendai virus Series Somatic Cell Sorting - Cell Movement Spinal Spinal Cord Staining method Stains Stem cells Subfamily lentivirinae T-Cell Activation Tacrolimus Technical Degree Techniques Time Validation Xenograft procedure base body system design fetal functional loss human disease immunosuppressed in vivo induced pluripotent stem cell injured mRNA tagging motor function recovery nerve stem cell preclinical efficacy preclinical safety prospective protocol development research study safety study treatment effect

项目摘要

DESCRIPTION (provided by applicant): The development and characterization of large animal models of specific human diseases and their effective utilization in preclinical efficacy and safety studies is essential for a successful transition of cell replacement- based therapies into clinic. Depending on the disease to be targeted, the duration of post-cell transplantation survival, and the need for use of transient or continuous immunosuppression, routine use of such models is associated with a variable degree of technical/technological difficulties. In addition to general consideration in using large animal models, specific limitations exist depending on the diseased organ system and associated functional loss to be studied. In the field of spinal neurodegenerative disorders, for example, several specific challenges remain, including: i) long-term maintenance of spinally injured animals with fully developed paraplegic phenotype, ii) reliable and safe immunosuppression protocols to be used in xenograft or allogeneic grafting design, and iii) the availability of inbred partially or fully MHC-matched animals for generation of isogeneic or allogeneic neural precursor lines (NSCs) to be used for in vivo grafting. In addition, cell labeling techniques which would permit to study time dependent changes in grafted cell survival/maturation in living animals and perform postmortem gene activity profiling in differentially generated cell populations (iPS-derived NSCs or fetal tissue-derived NSCs, for example) after grafting into a single animal recipient are not available. The development of these protocols/techniques is critical for optimization and validation of large preclinical models and cell derivation protocols to be used in perspective human trials. By using fully or partially MHC- matched miniature swine, we first propose to characterize the survival, differentiation and gene activity profile of established porcine iPS or fetal tissue-derived NSCs after grafting into the lumbar spinal cord in naïve non- immunosuppressed or transiently immunosuppressed swine. Second, using well characterized porcine model of spinal contusion injury, we will define the treatment effect after spinal grafting of isogeneic or allogeneic iPS an FT-derived NSCs on the recovery of motor function and corresponding grafted cell survival.

描述（通过应用提供）：特定人类疾病的大动物模型的发展和表征及其在临床前有效性和安全性研究中的有效利用对于成功过渡基于细胞的疗法至关重要。根据要针对的疾病，细胞移植后的存活持续时间以及使用瞬态或连续免疫抑制的需求，常规使用这种模型与技术/技术困难程度不同。除了使用大型动物模型的一般考虑外，还存在特定的局限性，具体取决于解剖器官系统和相关的功能损失。例如，在脊柱神经退行性疾病的领域中，仍然存在一些具体的挑战，包括：I）长期维持深处受伤的动物，具有完全发达的甲状腺术表型，ii）可靠且安全的免疫抑制协议，可用于元素或同种异体植物术，以及IS的全部或ISII的可用性），以及ISII的可用性）。用于体内移植的神经元前体系（NSC）。此外，在不同产生的细胞群体中（IPS衍生的NSC或胎儿组织衍生的NSC）中，将允许研究活动物中移植细胞存活/成熟的时间变化并在嫁接到单个动物后，将在不同生成的细胞群体中进行现状的细胞存活/成熟度变化，并在不同产生的细胞群体中进行死后基因活性谱分析，将其进行依赖的细胞标记技术。这些方案/技术的开发对于优化和验证大型临床前模型和细胞推导方案至关重要。通过使用完全或部分MHC匹配的微型猪，我们首先建议在嫁接到幼稚的非免疫抑制或暂时性化的不免疫抑制的腰椎中后，已建立的猪IP或胎儿组织衍生的NSC的生存，分化和基因活性谱。其次，使用良好的脊髓挫伤猪模型，我们将在脊髓植入脊髓或同种IP后定义治疗效果，该治疗效果是FT衍生的NSC在运动功能恢复和相应的移植细胞存活中的恢复。