Adipose Stem Cell Therapy for Krabbe Disease

描述(申请人提供)：Krabbe病是一种威胁生命的遗传性糖原储存疾病，由半乳脑苷酶(GALC)酶突变引起。唯一可用的治疗方法是在生命的最初几个月进行异基因骨髓移植，以在全身产生活性形式的GALC。骨髓移植并发移植物抗宿主病，这是一种严重的免疫疾病，其特征是移植的细胞毒性T淋巴细胞破坏宿主组织，包括皮肤上皮、肠粘膜和肾脏。GVHD的并发症延长了住院时间，增加了医疗费用，并具有较高的相关发病率和死亡率。如果克拉贝氏病的临床诊断晚于最初几个月，患者就没有有效的治疗选择，因为骨髓移植不再有效。我们的初步数据表明，GALC不仅在造血干细胞中表达，也在脂肪来源的干细胞中表达。基于这些重要的观察，我们建议检验以下最重要的假设：脂肪来源的干细胞(ASC)有潜力作为一种细胞治疗性表达GALC来治疗Krabbe病，而不会产生造血干细胞治疗的复杂破坏性后果。这一提议构成了下文概述的转化性和再生性医疗战略的初步概念验证步骤。对小鼠的研究是这一过程的第一步。最终，非人类灵长类动物模型将允许对我们的新型治疗干预进行分析，允许对动物进行多次活检、MRI分析和独特的途径，例如执行在低阶动物模型中无法完成的认知和行为测试的能力。此外，对非人类灵长类动物的治疗分析允许以几乎与人类临床试验相同的方式进行测试。我们的研究针对的是唯一可用的人类遗传病的非人类灵长类动物模型，并将提供在人类临床环境中无法从伦理上获得的基本信息，并对治疗因这种毁灭性疾病而受损的人类胎儿和婴儿具有直接重要性。公共卫生相关性：根据PAR-06-198“NINDS在翻译研究中的探索/发展项目”重新提交赠款。R21建议基于这样的假设，即脂肪来源的干细胞(ASC)有潜力作为一种细胞治疗性表达GALC用于治疗Krabbe病，而不会产生造血干细胞治疗的复杂破坏性后果。这项建议构成了全面的转化性和再生性医疗战略的初步概念证明步骤。具体地说，小鼠研究将是这一过程的第一步。随后在非人类灵长类动物模型中进行的原理研究的证明将允许通过对动物进行多次活检、MRI分析和独特的途径来分析我们的新的治疗干预措施，例如执行认知和行为测试的能力，这在低阶动物模型中是无法完成的。

DESCRIPTION (provided by applicant): Krabbe's disease is a life threatening, inherited glycogen storage disease resulting from mutations in the enzyme galactocerebrosidase (GALC). The only available therapy is heterologous bone marrow transplantation during the earliest months of life to produce the active form of GALC through out the body. Bone marrow transplantation is complicated by graft versus host disease, a severe immunological disorder characterized by engrafted cytotoxic T lymphocytes destruction of host tissues including the skin epithelium, intestinal mucosa, and kidneys. The complications of GVHD extend hospitalizations, increase medical costs, and have a high degree of associated morbidity and mortality. If the clinical diagnosis of Krabbe's disease is made later than the first few months, there is no effective treatment option for patients, as bone marrow transplant is no longer effective. Our Preliminary data indicates that GALC is expressed not only by hematopoietic stem cells but also by adipose derived stem cells. Based on these important observations, we propose to test the following overarching hypothesis: That adipose derived stem cells (ASC) have the potential to serve as a cell therapeutic expressing GALC for Krabbe's disease without the complicating destructive consequences of hematopoietic stem cell therapy. This proposal constitutes the initial proof of concept step in the translational and regenerative medical strategy outlined below. The murine studies are the first step in this process. Eventually, the nonhuman primate model will allow the analysis of our novel therapeutic interventions by permitting multiple biopsies, MRI analysis of animals and unique avenues, such as the ability to perform both cognitive and behavioral testing that cannot be done in lower order animal models. Additionally, the analysis of therapies in nonhuman primates permits the testing to be performed in a manner nearly identical to a human clinical trial. Our investigations are directed towards the only available nonhuman primate model of a human genetic disease, and will provide essential information that cannot be ethically obtained in a human clinical setting, and are of direct importance for the treatment of human fetuses and infants compromised by this devastating disease. PUBLIC HEALTH RELEVANCE: The grant is resubmitted in response to PAR-06-198 "NINDS Exploratory / Developmental Projects in Translational Research". This R21 proposal rests on the hypothesis that adipose derived stem cells (ASC) have the potential to serve as a cell therapeutic expressing GALC for Krabbe's disease without the complicating destructive consequences of hematopoietic stem cell therapy. This proposal constitutes the initial proof of concept step in a comprehensive translational and regenerative medical strategy. Specifically, murine studies will serve as the first step in this process. Subsequent proof of principle studies in a nonhuman primate model will allow the analysis of our novel therapeutic interventions by permitting multiple biopsies, MRI analysis of animals and unique avenues, such as the ability to perform both cognitive and behavioral testing, that cannot be done in lower order animal models.