Correction of neural abnormalities in Hurler syndrome

描述（由申请人提供）：进行性神经功能障碍和 智力迟钝是Hurler最具破坏性的后果之一 综合征（粘多糖样沉积症I型），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 神经心理异常不能通过 造血干细胞移植（通过骨髓移植; BMT）。 研究人员最近丰富和扩大了一个非造血， 来自出生后人骨髓的多能间充质干细胞（MSC）， 它可以在体外分化成各种类型的神经元和神经胶质细胞， 细胞以及多种中胚层谱系细胞。 因此可能 可以使用这些细胞重建神经元和多种其他组织 从骨髓中提取 这些研究的长期目标是开发一种新的 通过以下方法矫正神经异常的治疗策略 将MSC或其后代移植到中枢神经系统中。 Hurler综合征将被用作开发该策略的模型，因为（i） Hurler综合征是最常见的粘多糖样变性，（ii）大量 的骨髓样本，因为病人转介到 研究者的BMT中心，以及（iii）临床应用的潜力 在研究者庞大的患者基础上进行跨国研究。 如果 成功的类似策略可能对治疗其他 BMT不能停止的糖胺聚糖代谢的储存障碍 进行性神经功能恶化 使用MSC的主要优点 （而不是神经干细胞）用于开发治疗策略， 这些细胞（i）可以容易地从小的骨髓抽吸物中获得 样品，（ii）可以用基因以高效率转导，而不会损失 干细胞能力，（iii）支持持续基因表达，和（iv） 不受与使用人类胚胎干细胞相关的伦理问题的影响 细胞或胎儿神经元干细胞。 因此，MSC可能是理想的类型。 用于在疾病中临床递送治疗性基因的自体细胞 如Hurler综合征。 在本申请中，研究人员建议 为实现这一目标开展研究。 在目前的小额赠款申请中， 研究人员将专注于体外研究人MSC来源于 正常和Hurler骨髓。 他们将比较结构和约束力 从Hurler和正常MSC的硫酸乙酰肝素的性质，鉴定 Hurler细胞中异常糖胺聚糖导致 来源于MSC的神经细胞的分化缺陷，并检查 正常或基因校正的MSC的存在可以纠正这些异常。 的 研究人员还将检查MSC是否能成功植入 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 提出了 研究人员预计，这些研究产生的数据 将导致随后提交传统的研究资助， 应用，他们将这些研究扩展到动物模型， Hurler综合征，如MPS-I小鼠，作为未来人类的先决条件 审判

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.