Adipose Stem Cell Therapy for Krabbe Disease

克拉伯病的脂肪干细胞疗法

• 批准号: 7912741
• 负责人: Bruce A. Bunnell
• 金额: $ 9.31万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912741
• 关键词: Abbreviations; Adipocytes; Adipose tissue; Allogenic; Animal Model; Animals; Antigens; Biological Assay; Biomedical Research; Biopsy; Bone Marrow Transplantation; Brain; Bromodeoxyuridine; Cell Extracts; Cells; Chorionic Villi Sampling; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Colony-forming units; Complementary DNA; Cytotoxic T-Lymphocytes; Data; Deoxyuridine; Development; Disease; Dose; Engineering; Enzymes; Epithelium; Fetus; Fibroblasts; Frequencies; Gait; Genetic Engineering; Globoid cell leukodystrophy; Glycogen Storage Disease; Glycosphingolipids; Goals; Grant; Green Fluorescent Proteins; Hematopoietic stem cells; Hereditary Disease; Histocompatibility; Histopathology; Hospitalization; Human; Human Genetics; Immunohistochemistry; In Situ; Infant; Inherited; Intestinal Mucosa; Intravenous; Intraventricular Injections; Investigation; Kidney; Knowledge; Lentivirus Vector; Life; Life Expectancy; Live Birth; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Medical; Mesenchymal Stem Cells; Methodology; Modeling; Morbidity - disease rate; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Neural Conduction; Neuraxis; Newborn Infant; Outcome; Pathology; Patients; Peripheral Blood Mononuclear Cell; Polyacrylamide Gel Electrophoresis; Pre-Clinical Model; Primates; Process; Psychosine; Research; Rest; Rotarod Performance Test; Safety; Skin; Stem cell transplant; Stem cells; Symptoms; Testing; Therapeutic; Tissues; Translational Research; Transplantation; Treatment Efficacy; Umbilical Cord Blood; United States Food and Drug Administration; Work; X-Ray Computed Tomography; base; behavior test; clinical Diagnosis; cost; effective therapy; galactosylceramidase; graft vs host disease; graft vs host reaction; lateral ventricle; mortality; neuromuscular; nonhuman primate; novel therapeutic intervention; pre-clinical; public health relevance; regenerative; response; stem cell therapy

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.

描述（由申请人提供）：Krabbe病是一种威胁生命的，遗传性糖原储存疾病，这是由于酶半乳糖酶繁殖酶（GALC）突变引起的。唯一可用的疗法是生命最早的几个月中异源的骨髓移植，以产生整个身体的galc的活跃形式。骨髓移植因移植物与宿主疾病而复杂，这是一种严重的免疫疾病，其特征是植入了细胞毒性T淋巴细胞的破坏宿主组织，包括皮肤上皮，肠粘膜和肾脏。 GVHD的并发症扩大了住院，增加医疗费用，并具有高度相关的发病率和死亡率。如果对Krabbe病的临床诊断比最初的几个月晚，则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不仅用造血干细胞表达，而且表达了脂肪衍生的干细胞。基于这些重要的观察，我们建议测试以下基本假设：脂肪衍生的干细胞（ASC）具有作为Krabbe病的细胞治疗性表达galc的潜力，而没有造血干细胞治疗的破坏性后果。该提案构成了以下概述的转化和再生医学策略中概念步骤的最初证明。鼠研究是此过程的第一步。最终，非人类灵长类动物模型将通过允许多次活检，对动物的MRI分析和独特的途径进行分析，例如执行在低阶动物模型中无法进行认知和行为测试的能力。此外，对非人类灵长类动物的疗法的分析允许以几乎与人类临床试验相同的方式进行测试。我们的调查针对人类遗传疾病的唯一可用的非人类灵长类动物模型，并将提供基本信息，这些信息在人类临床环境中无法在道德上获得，并且对于治疗这种毁灭性的人类胎儿和婴儿至关重要疾病。公共卫生相关性：该赠款是针对198年6月6日的“转化研究中的Ninds探索 /发展项目”重新提交的。该R21提案基于以下假设：脂肪衍生的干细胞（ASC）具有作为Krabbe病的细胞治疗表达galc的潜力，而没有造血干细胞疗法的破坏性后果的复杂性。该建议构成了综合翻译和再生医学策略中概念步骤的初步证明。具体而言，鼠研究将作为此过程的第一步。随后在非人类灵长类动物模型中的原则研究证明将通过允许多次活检，动物的MRI分析和独特的途径（例如执行认知和行为测试的能力）来分析我们的新型治疗干预措施，这是不能在较低的情况下进行的。订购动物模型。

项目成果

High-throughput screening of stem cell therapy for globoid cell leukodystrophy using automated neurophenotyping of twitcher mice.

• DOI: 10.1016/j.bbr.2012.08.020
• 发表时间: 2013-01-01
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Scruggs, Brittni A.;Bowles, Annie C.;Zhang, Xiujuan;Semon, Julie A.;Kyzar, Evan J.;Myers, Leann;Kalueff, Allan V.;Bunnell, Bruce A.
• 通讯作者: Bunnell, Bruce A.