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Mechanisms for immune tolerance in Pompe Disease

庞贝病的免疫耐受机制

基本信息

批准号：
7911737
负责人：
Dwight D Koeberl
金额：
$ 45.96万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-12 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911737
关键词：
Acids Actins Adjuvant Affect Alpha-glucosidase Anaphylaxis Antibodies Antibody Formation Biological Models Capsid Capsid Proteins Cells Chickens Clinical Trials Cytomegalovirus Cytotoxic T-Lymphocytes Disease Dose Early Diagnosis Enhancers Future Glycogen Glycogen storage disease type II Health Benefit Human Immune Tolerance Immune response Immune system Immunity Immunoglobulins Immunologics Immunosuppression Interleukin-10 Interleukin-4 Interleukin-5 Knock-out Knockout Mice Knowledge Kupffer Cells Liver Measures Mediating Mediator of activation protein Methotrexate Mus Natural Immunity Neonatal Screening Patients Play Proteins Public Health Receptor Signaling Recombinants Regulatory T-Lymphocyte Replacement Therapy Risk Role Signal Transduction Signaling Molecule Skeletal Muscle T cell response T-Lymphocyte Subsets Toll-like receptors Transgenes Translating Up-Regulation Viral Vector adeno-associated viral vector base clinical application cytokine desensitization design effective therapy enzyme replacement therapy gene therapy immunogenic improved innovation insight killer T cell mortality neutralizing antibody pre-clinical prevent promoter research study response transgene expression treatment strategy vector

项目摘要

REVISED 3/21/2009 - Newborn screening for Pompe disease is available and enzyme replacement therapy (ERT) with human acid alpha glucosidase (hGAA) is effective, ifERT is started early and immune tolerance is present. Knowledge of the mechanisms for immune tolerance to hGAA in Pompe disease will guide the design of future clinical trials for Pompe disease and other lysosomal storage disorders.Wepropose to use an innovative strategy to express hGAA in the liver that simultaneously leads to immune tolerance to hGAA and long lasting efficacy from ERT in Pompe disease mice. Using these model systems, we will investigate the immunologic mechanisms required to induce immune tolerance in GAA-null mice, and evaluate the impact of immune tolerance on efficacy of ERT or gene therapy. This strategy can be translated to clinical applications very readily, because unlike other gene therapy approaches the vector dose is very low, risks are similarly low, and potential benefits are great.General Hypothesis: Liver-specific expression of hGAA will induce immune tolerance and enhance the efficacy of replacement therapy (ERT and/or gene therapy) in Pompe disease. Specific Aim 1 will evaluate mechanisms responsible for the induction of immune tolerance to hGAA by Pompe disease. Liver-specific expression of hGAA with a tolerogenic AAV vector will establish immune tolerance in GAA-null mice. Immune tolerance to hGAA will be demonstrated via challenges with recombinant hGAA and adjuvant. The role of key players of the adaptive immune response, including Treg cells and NKT cells, will be examined in the presence or absence of immune tolerance. Treg cell depletion will prevent immune tolerance to hGAA. Specific Aim 2 will demonstrate that efficacy of the hGAA therapy can be improved by modulating the immune response to hGAA. A dose reduction experiment with tolerogenic vector will determine a lower threshold for achieving immune tolerance to hGAA. Long-term efficacy from ERT will be enhanced by immune tolerance, because adaptive immune responses will be abrogated by the less immunogenic transgene. The benefit of immune tolerance to hGAA will be demonstrated by evaluating ERT in GAA-null mice that received low-dose tolerogenic vector. We will evaluate an innovative approach to immunodulatory gene therapy, consisting of desensitization to the hGAA protein by the administration of low-dose tolerogenic vector to mice that previously formed antibodies to hGAA. Desensitization prevents mortality from anaphylaxis during ERT in antibody-positive GAA-null mice. These comparisons will guide preclinical experiments to further immunomodulatory gene therapy in Pompe disease and other lysosomal storage disorders.

2009 年 3 月 21 日修订 - 可以进行新生儿庞贝病筛查，并且如果早期开始 ERT 且存在免疫耐受，则使用人酸性 α 葡萄糖苷酶 (hGAA) 进行酶替代疗法 (ERT) 是有效的。了解庞贝病对 hGAA 的免疫耐受机制将指导庞贝病和其他溶酶体贮积症未来临床试验的设计。我们建议使用一种创新策略在肝脏中表达 hGAA，同时在庞贝病小鼠中产生对 hGAA 的免疫耐受和 ERT 的长期疗效。使用这些模型系统，我们将研究在 GAA 缺失小鼠中诱导免疫耐受所需的免疫机制，并评估免疫耐受对 ERT 或基因治疗疗效的影响。这种策略可以很容易地转化为临床应用，因为与其他基因治疗方法不同，载体剂量非常低，风险也很低，潜在的好处也很大。一般假设：hGAA 的肝脏特异性表达将诱导免疫耐受并增强庞贝病替代疗法（ERT 和/或基因疗法）的疗效。具体目标 1 将评估庞贝病诱导 hGAA 免疫耐受的机制。 hGAA 与耐受性 AAV 载体的肝脏特异性表达将在 GAA 缺失小鼠中建立免疫耐受。对 hGAA 的免疫耐受将通过重组 hGAA 和佐剂的挑战来证明。 The role of key players of the adaptive immune response, including Treg cells and NKT cells, will be examined in the presence or absence of immune tolerance. Treg 细胞耗竭将阻止对 hGAA 的免疫耐受。具体目标 2 将证明 hGAA 疗法的功效可以通过调节对 hGAA 的免疫反应来提高。使用致耐受性载体进行剂量减少实验将确定实现 hGAA 免疫耐受的较低阈值。 ERT 的长期疗效将通过免疫耐受得到增强，因为适应性免疫反应将被免疫原性较低的转基因所消除。对 hGAA 免疫耐受的益处将通过评估接受低剂量致耐受性载体的 GAA 缺失小鼠的 ERT 来证明。我们将评估免疫调节基因治疗的创新方法，包括通过向先前形成 hGAA 抗体的小鼠施用低剂量致耐受性载体来使 hGAA 蛋白脱敏。脱敏可防止抗体阳性 GAA 缺失小鼠在 ERT 期间因过敏反应而死亡。这些比较将指导临床前实验进一步针对庞贝病和其他溶酶体贮积症进行免疫调节基因治疗。