Correction of neural abnormalities in Hurler syndrome

Hurler 综合征神经异常的纠正

• 批准号: 6417151
• 负责人: Pankaj GUPTA
• 金额: $ 6.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6417151
• 关键词: NOD mouse; SCID mouse; biotechnology; bone marrow; bone marrow transplantation; carbohydrate metabolism; cell differentiation; chemical binding; chemical structure; gene therapy; genetic manipulation; glia; heparan sulfate; human subject; inborn carbohydrate metabolism disorder; mental retardation; mesenchyme; mixed tissue /cell culture; mucopolysaccharides; mucopolysaccharidosis type I; nervous system disorder; nervous system disorder therapy; neurons; patient oriented research; stem cell transplantation; stem cells; technology /technique development

DESCRIPTION (provided by applicant): Progressive neurological dysfunction and mental retardation are among the most devastating consequences of Hurler syndrome (mucopolysaccharidosis type I), the most common inherited disorder of glycosaminoglycan metabolism usually diagnosed in early childhood. These neuro-psychological abnormalities are not adequately corrected by hematopoietic stem cell transplantation (via bone marrow transplantation; BMT). The investigators recently enriched and expanded a non-hematopoietic, multipotent mesenchymal stem cell (MSC) from post-natal human bone marrow, which can be differentiated in vitro into various types of neuronal and glial cells as well as multiple mesodermal lineage cells. It may therefore be possible to reconstitute neuronal and diverse other tissues using such cells from the bone marrow. The long term goal of the studies is to develop a novel therapeutic strategy for the correction of neurological abnormalities by transplantation of MSC or their progeny into the central nervous system. Hurler syndrome will be used as a model for developing this strategy since (i) Hurler syndrome is the most common mucopolysaccharidosis, (ii) a large number of bone marrow samples are available because of referral of patients to the investigators' center for BMT, and (iii) the potential for clinical transnational studies in the investigators' large patient base. If successful, similar strategies may potentially be useful for treating other storage disorders of glycosaminoglycan metabolism in which BMT does not halt progressive neurological deterioration. The major advantages of using MSCs (rather than neuronal stem cells) for developing a therapeutic strategy are that these cells (i) can easily be obtained from a small bone marrow aspirate sample, (ii) can be transduced with genes with high efficiency without loss of stem cell capability, (iii) support sustained gene expression, and (iv) are not subject to ethical issues associated with the use of human embryonic stem cells or fetal neuronal stem cells. MSCs may thus be the ideal type of autologous cell for the clinical delivery of therapeutic genes in disorders such as Hurler syndrome. In this application, the investigators propose to initiate studies towards this goal. In the current Small Grant application, the investigators will focus on in vitro studies of human MSC derived from normal and Hurler bone marrow. They will compare the structure and binding properties of heparan sulfates from Hurler and normal MSC, identify the mechanism(s) by which abnormal glycosaminoglycas in Hurler cells lead to defective differentiation of neural cells derived from MSC, and examine if the presence of normal or gene corrected MSC can rectify these abnormalities. The investigators will also examine if MSC can be successfully implanted into brains of NOD/SCID mice. They have preliminary data supporting this hypothesis, and indicating that they can successfully perform the studies proposed. The investigators anticipate that data generated from these studies will lead to the subsequent submission of a traditional research grant application, in which they will extend these studies to animal models of Hurler syndrome such as the MPS-I mouse, as a prerequisite for future human trials.

描述（由申请人提供）：进行性神经功能障碍和 精神障碍是 Hurler 最具破坏性的后果之一 综合征（I 型粘多糖贮积症），最常见的遗传性疾病 糖胺聚糖代谢通常在儿童早期诊断。 这些 神经心理异常没有得到充分纠正 造血干细胞移植（通过骨髓移植； 骨髓移植）。 研究人员最近丰富并扩展了一种非造血、 来自出生后人骨髓的多能间充质干细胞（MSC）， 可在体外分化为各种类型的神经元和神经胶质细胞 细胞以及多个中胚层谱系细胞。 因此可能是 可以使用此类细胞重建神经元和多种其他组织 来自骨髓。 研究的长期目标是开发一种新颖的 纠正神经系统异常的治疗策略 将 MSC 或其后代移植到中枢神经系统。 Hurler 综合症将被用作制定该策略的模型，因为 (i) Hurler 综合征是最常见的粘多糖贮积症，(ii) 大量 由于将患者转诊至骨髓样本 BMT 研究人员中心，以及 (iii) 临床应用的潜力 针对研究人员庞大的患者群体进行的跨国研究。 如果 成功的类似策略可能有助于治疗其他疾病 BMT 不停止的糖胺聚糖代谢储存障碍 进行性神经功能恶化。 使用 MSC 的主要优势 （而不是神经元干细胞）用于制定治疗策略 这些细胞 (i) 可以很容易地从少量骨髓抽吸物中获得 样品，(ii)可以高效地转导基因而不会损失 干细胞能力，(iii) 支持持续的基因表达，以及 (iv) 不受与使用人类胚胎干相关的伦理问题的影响 细胞或胎儿神经元干细胞。 因此，间充质干细胞可能是理想的类型 用于临床传递疾病治疗基因的自体细胞 比如赫勒综合症。 在本申请中，研究人员建议 朝着这个目标发起研究。 在当前的小额赠款申请中， 研究人员将重点关注来自以下来源的人类 MSC 的体外研究： 正常和Hurler 骨髓。 他们将比较结构和结合 来自 Hurler 和正常 MSC 的硫酸乙酰肝素的特性，确定 Hurler 细胞中糖胺聚糖异常导致的机制 MSC 衍生的神经细胞分化缺陷，并检查是否 正常或基因校正的 MSC 的存在可以纠正这些异常。 这 研究人员还将检查间充质干细胞是否可以成功植入 NOD/SCID 小鼠的大脑。 他们有初步数据支持这一点 假设，并表明他们可以成功地进行研究 建议的。 研究人员预计这些研究产生的数据 将导致随后提交传统研究补助金 应用，他们将把这些研究扩展到动物模型 Hurler 综合征，例如 MPS-I 小鼠，是未来人类的先决条件 试验。