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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-新生儿庞贝氏症筛查可用，如果早期开始酶替代疗法（ERT）且存在免疫耐受，则使用人酸性α-葡萄糖苷酶（hGAA）的ERT有效。对庞贝氏症中hGAA免疫耐受机制的了解将指导未来庞贝氏症和其他溶酶体贮积症临床试验的设计，我们建议使用一种创新的策略，在肝脏中表达hGAA，同时导致对hGAA的免疫耐受和对庞贝氏症小鼠的ERT的长期持久疗效。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或基因治疗功效的影响。这种策略可以很容易地转化为临床应用，因为不像其他基因治疗方法的载体剂量是非常低的，风险同样低，和潜在的好处是巨大的。一般假设：肝脏特异性表达的hGAA将诱导免疫耐受和增强疗效的替代疗法（ERT和/或基因治疗）在庞贝氏症。具体目标1将评价庞贝氏症诱导对hGAA免疫耐受的机制。用致耐受性AAV载体肝特异性表达hGAA将在GAA缺失小鼠中建立免疫耐受。将通过用重组hGAA和佐剂激发来证明对hGAA的免疫耐受性。将在存在或不存在免疫耐受的情况下检查适应性免疫应答的关键参与者（包括Treg细胞和NKT细胞）的作用。Treg细胞耗竭将阻止对hGAA的免疫耐受。具体目标2将证明hGAA疗法的功效可通过调节对hGAA的免疫应答来改善。用致耐受性载体的剂量降低实验将确定实现对hGAA的免疫耐受性的较低阈值。免疫耐受将增强ERT的长期疗效，因为免疫原性较低的转基因将消除适应性免疫应答。将通过在接受低剂量致耐受性载体的GAA缺失小鼠中评价ERT来证明对hGAA的免疫耐受性的益处。我们将评估一种创新的免疫调节基因治疗方法，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对hGAA蛋白脱敏。在抗体阳性GAA缺失小鼠中，脱敏可防止ERT期间过敏反应导致的死亡。这些比较将指导临床前实验，以进一步免疫调节基因治疗庞贝氏症和其他溶酶体贮积症。