Stem Cell Transplantation for Neurogenetic Disease

遗传性代谢紊乱导致大量脑部疾病。治疗这种疾病的主要障碍是 疾病的一个重要特征是缺陷的固有性质导致病理性病变在体内的全球分布， 这种情况要求在CMS中或在关键区域纠正单元格， 病理后果最为严重。在这项资助中，我们将研究基于神经干细胞（NSC）的 通过递送可扩散的药物来治疗神经遗传性疾病中的中枢神经系统（CMS）的方法 大脑中的蛋白质。该方法是在体外对神经干细胞的缺陷进行遗传校正， 将纠正过的细胞移植回有缺陷的大脑。在适当的情况下，NSC可以在 大脑并分化成所有三种主要的脑细胞谱系。作为测试系统，我们将使用B- 在一个实施方案中，使用葡萄糖醛酸酶（GUSB）缺陷型小鼠，其是人溶酶体贮积病（LSD）的模型。 有超过50个个体LSD，它们负责所有遗传儿童的约20% 影响CMS的遗传疾病。原则上，对于> 90%的 LSD的。它是基于这样的观察，即溶酶体酶可以从遗传校正的 细胞，扩散通过组织，并可以采取由突变细胞恢复丢失的酶活性。 因此，将修饰的NSC仅递送至脑的一小部分可能能够挽救大量的脑损伤。 脑组织为了实现治疗性酶的全球递送，移植的细胞需要 分散在大脑的三维空间中。我们已经证明基因治疗可以 使用克隆细胞系在GUSB缺陷小鼠的大脑中起作用。然而， 实现永久和完全的矫正，特别是在达到更大的全球病变 人脑本研究拟探讨：1）转基因植物的移植特性及载体基因在转基因植物中的表达。 原代鼠NSC作为自体校正（体内基因治疗）的模型; 2） 增加NSC远离注射部位的迁移;和3）治疗对 神经病理学和移植受者的安全性。移植研究进展 在该模型中用于治疗的NSC的性质应该适用于整个疾病类别。

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 CMS.This circumstance requires that cells be corrected either throughout the CMSor 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 (CMS) 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 CMS. 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-deficinet 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.