Stem Cell Transplantation for Neurogenetic Disease

干细胞移植治疗神经遗传性疾病

• 批准号: 7872768
• 负责人: JOHN H WOLFE
• 金额: $ 35.26万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872768
• 关键词: Advanced Development; Affect; Animal Model; Animals; Area; Autologous; Back; Beta-glucuronidase; Brain; Brain Diseases; Cell Line; Cell Transplants; Cells; Childhood; Defect; Diffuse; Disease; Engineering; Engraftment; Enzymes; Gene Delivery; Gene Expression; Genes; Grant; Hereditary Disease; Human; In Vitro; Individual; Inherited; Injection of therapeutic agent; Lentivirus Vector; Lesion; Lysosomal Storage Diseases; Marrow; Metabolic; Metabolic Diseases; Modeling; Morphology; Mucopolysaccharidosis VII; Mus; Mutation; Nature; Neocortex; Neuraxis; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Patients; Pattern; Property; Proteins; Relative (related person); Safety; Signal Transduction; Site; Spatial Distribution; Stem cell transplant; Stromal Cells; System; Testing; Time; Tissues; Transplant Recipients; Transplantation; Treatment Effectiveness; Work; base; brain cell; brain tissue; cellular engineering; common treatment; expression vector; gene therapy; human disease; migration; mutant; nerve stem cell; neurogenetics; neuropathology; novel; progenitor; research study; therapeutic enzyme; treatment strategy; vector

DESCRIPTION (provided by applicant): Inherited metabolic disorders cause a significant number of brain diseases. A major barrier to treating such diseases is that the inherent nature of the defect results in global distribution of the pathologic lesions within the CNS. This circumstance requires that cells be corrected either throughout the CNS or in key areas where the pathologic consequences are most severe. In this grant we will investigate neural stem cell (NSC)-based approaches to treat the central nervous system (CNS) in neurogenetic disease by delivering a diffusible protein within the brain. The approach is to genetically correct the defect in NSCs in vitro and transplant the corrected cells back into the defective brain. Under the right circumstances, NSCs can migrate within the brain and differentiate into all three major lineages of brain cells. As a test system, we will use a B- glucuronidase (GUSB) deficient mouse, which is a model for human lysosomal storage diseases (LSD). There are >50 individual LSDs and they are responsible for approximately 20% of all inherited childhood genetic diseases that affect the CNS. A common treatment strategy can be used, in principle, for >90% of the LSD's. It is based on the observation that lysosomal enzymes can be secreted from genetically corrected cells, diffuse through tissue, and can be taken up by mutant cells to restore the missing enzymatic activity. Thus, delivery of the modified NSC's to only a fraction of the brain may be able to rescue a large amount of brain tissue. To achieve global delivery of the therapeutic enzyme, the transplanted cells need to be dispersed within the three dimensional space of the brain. We have demonstrated that gene therapy can work in the brains of the GUSB-deficient mice using a clonal cell line. However, there are substantial barriers to achieving permanent and complete correction, particularly in reaching the global lesions in the much larger human brain. We propose to investigate: 1) the transplantation properties and vector gene expression in primary murine NSC's as a model for autologous correction (en vivo gene therapy); 2) potential strategies to increase the migration of the NSC's away from the injection site; and 3) the effectiveness of the treatment on the neuropathology and the safety of the transplant recipients. Advances in understanding the transplantation properties of NSC's for treatment in this model should have applicability to the whole class of disease.

描述（由申请人提供）：遗传性代谢紊乱导致大量脑部疾病。治疗此类疾病的一个主要障碍是缺陷的固有性质导致中枢神经系统内病理病变的整体分布。这种情况需要对整个中枢神经系统或病理后果最严重的关键区域的细胞进行纠正。在这笔资助中，我们将研究基于神经干细胞（NSC）的方法，通过在大脑内传递可扩散的蛋白质来治疗神经遗传性疾病中的中枢神经系统（CNS）。该方法是在体外对神经干细胞的缺陷进行基因纠正，并将纠正后的细胞移植回有缺陷的大脑中。在适当的情况下，神经干细胞可以在大脑内迁移并分化成脑细胞的所有三个主要谱系。作为测试系统，我们将使用 B-葡萄糖醛酸酶 (GUSB) 缺陷小鼠，它是人类溶酶体贮积病 (LSD) 的模型。存在超过 50 种 LSD，它们导致了影响中枢神经系统的所有遗传性儿童遗传疾病的大约 20%。原则上，超过 90% 的 LSD 可以使用常见的治疗策略。它基于这样的观察：溶酶体酶可以从基因校正的细胞中分泌，通过组织扩散，并且可以被突变细胞吸收以恢复缺失的酶活性。因此，仅将修饰后的 NSC 递送到大脑的一小部分可能能够挽救大量的脑组织。为了实现治疗酶的全局递送，移植的细胞需要分散在大脑的三维空间内。我们已经证明，基因疗法可以使用克隆细胞系在 GUSB 缺陷小鼠的大脑中发挥作用。然而，实现永久和完全的矫正存在很大的障碍，特别是在到达更大的人脑中的整体病变方面。我们建议研究：1）原代小鼠 NSC 的移植特性和载体基因表达，作为自体校正（体内基因治疗）的模型； 2) 增加 NSC 远离注射部位迁移的潜在策略； 3) 治疗对神经病理学的有效性和移植受者的安全性。在理解该模型中用于治疗的 NSC 移植特性方面取得的进展应该适用于整个疾病类别。