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.

修订后的3/21/2009-提供了庞贝疾病的新生儿筛查，并使用人酸α葡萄糖酶（HGAA）有效，酶替代疗法（ERT）有效，IFERT早期开始且具有免疫耐受性。 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.使用这些模型系统，我们将研究诱导GAA无效小鼠免疫耐受性所需的免疫机制，并评估免疫耐受性对ERT或基因治疗疗效的影响。该策略可以非常容易地转化为临床应用，因为与其他基因疗法方法不同，矢量剂量非常低，风险类似，潜在的好处也很大。一般假设：HGAA的肝特异性表达HGAA将诱导免疫耐受性并提高替代疗法的功效（ERT和/或Gene疗法）。具体目标1将评估负责通过庞贝疾病诱导HGAA免疫耐受性的机制。 HGAA具有耐受性AAV载体的HGAA的肝特异性表达将在GAA-NULL小鼠中建立免疫耐受性。对HGAA的免疫耐受性将通过重组HGAA和辅助的挑战来证明。在存在或不存在免疫耐受性的情况下，将检查自适应免疫反应的主要参与者，包括Treg细胞和NKT细胞。 Treg细胞耗竭将防止对HGAA的免疫耐受性。具体的目标2将表明，通过调节对HGAA的免疫反应，可以提高HGAA疗法的功效。与耐受性载体的剂量还原实验将确定较低的阈值实现对HGAA的免疫耐受性。免疫耐受性将增强ERT的长期功效，因为免疫原性转基因将消除适应性免疫反应。通过评估接收低剂量耐受性载体的GAA无效小鼠的ERT，可以证明对HGAA免疫耐受性的好处。我们将评估一种免疫调节基因疗法的创新方法，该方法包括对HGAA蛋白的脱敏，通过对先前形成HGAA抗体的小鼠的低剂量耐受性载体的施用。脱敏会阻止在抗体阳性GAA-NULL小鼠中ERT期间过敏反应的死亡率。这些比较将指导临床前实验，以进一步在庞贝疾病和其他溶酶体储存障碍中进行免疫调节基因治疗。