Stem Cell-Based Therapy for Canavan Disease

 描述(由申请人提供)： 人类神经干细胞在治疗神经退行性疾病方面具有相当大的潜力。这项提案概述了一系列旨在验证干细胞移植作为治疗目前难治性遗传性心脏病的可行治疗选择的实验。 儿童脑白质营养不良症(CD)。在与干细胞公司的合作中，我们已经产生了初步数据，证明了人类神经干细胞(HuCNS-SC)在CD动物模型中的成功植入。值得注意的是，在成年(3个月大)的动物中观察到了高水平的植入，这被认为具有相当大的临床相关性。通过HuCNS-SC干预和小鼠少突胶质前体细胞(MOPC)干预的对比，我们发现人类材料通过支持内源性少突胶质细胞发生来促进表型恢复，我们推测这种作用是由于局部微环境的营养效应所致。在此模型系统已发表工作的基础上，我们假设HuCNS-SC通过减少氧化应激造成的损伤，从而提高少突胶质细胞的活力来影响这种支持。因此，这项研究将量化移植动物中的关键代谢物，这些代谢物之前已经被我们的小组证明是CD表型的核心。这一重点在两个重要方面与当前的战略有很大不同。首先，关于氧化完整性的FOU与以往只关注于 寻求增加CD中天冬氨酸酯酶功能丧失的策略。其次，我们认为，任何寻求治疗症状性CD的策略都必须考虑到在这个项目中采用的模型系统中显而易见的严重的少突胶质细胞丢失，并且唯一真正可行的策略是那些可以直接处理这种有限的病理学特征的策略。这项研究将为主办机构的研究生和本科生提供机会，在长期致力于翻译性CD研究的研究人员的指导下，进行非常有希望的治疗干预。

 DESCRIPTION (provided by applicant): Human neural stem cells hold considerable potential for the treatment of neurodegenerative disease. This proposal outlines a series of experiments designed to validate stem cell transplantation as a viable therapeutic option for treatment of the currently intractable inherited pediatric leukodystrophy Canavan disease (CD). In collaboration with Stem Cells Inc. we have generated preliminary data demonstrating the successful engraftment of human neural stem cells (HuCNS-SC) in an animal model of CD. Significantly, high levels of engraftment were observed in adult (3 month old) animals, which is considered to be of considerable clinical relevance. By comparing HuCNS-SC intervention side by side with murine oligodendrocyte progenitor (mOPC) intervention, we show that human material promotes phenotypic recovery by way of the support of endogenous oligodendrogenesis, and we hypothesize here that this effect is due to trophic effects exerted on the local microenvironment. On the basis of previously published work in this model system, we posit that HuCNS-SC effect this support by way of a reduction in damage resulting from oxidative stress, with a consequent improvement in oligodendrocyte viability. Accordingly, this study will quantify key metabolites in transplanted animals that have been previously shown by our group to be central to the CD phenotype. This point of focus differs significantly from current strategies in two important ways. Firstly, the fous on oxidative integrity is a significant departure from previous studies that have focused solely on strategies that seek to augment the loss of aspartoacylase function in CD. Secondly, we argue that any strategy seeking to treat symptomatic CD must account for the profound oligodendrocyte loss that is readily apparent in the model system to be employed in this project, and that the only truly viable strategies are those that can address this limiting feature of pathology directly. This study will provide graduate and undergraduate students at the host institution with the opportunity to work with an extremely promising therapeutic intervention under the mentorship of an investigator with a long standing commitment to translational CD research.