Blocking the immune response to HDAd for Hemophilia A gene therapy

阻断 HDAd 的免疫反应以进行 A 型血友病基因治疗

基本信息

批准号：
8604405
负责人：
Masataka Suzuki
金额：
$ 24.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-10 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604405
关键词：
A Mouse Acute Address Adenovirus Vector Animal Model Animals Antibody Formation Attenuated Blood Blood Coagulation Disorders Canis familiaris Cell Cycle Cells Chronic Clinic Clinical Clinical Research Clinical Treatment Clinical Trials Coagulation Process Code Data Development Dose Excision Factor VIII Feedback Future Gene Deletion Gene Expression Generations Genes Genome Goals Half-Life Hematological Disease Hemofiltration Hemophilia A Human Hybrids Immune Immune response Immune system Immunosuppression Immunosuppressive Agents In Vitro Inborn Errors of Metabolism Inflammatory Inflammatory Response Injection of therapeutic agent Interferon Type I Intervention Lead Liver Mediating Medicine Mentors Methods Modeling Modification Molecular Morbidity - disease rate Mus Papio Patients Phase Platelet Count measurement Play Preparation Production Proteins Receptor Signaling Recombinants Replacement Therapy Reporting Research Personnel Role Senior Scientist Sepsis Signal Transduction System Therapeutic Effect Therapeutic Index Toll-like receptors Toxic effect Transgenes Translating Translations Treatment Efficacy Treatment Factor Viral Viral Genes abstracting attenuation blood treatment cell type clinically relevant college combinatorial cost cytokine design gene therapy helper-dependent adenoviral vector human F8 protein improved in vivo inhibitor/antagonist mortality nonhuman primate novel peripheral blood pre-clinical research study response safety study success therapeutic gene therapeutic transgene transgene expression vector von Willebrand Factor

项目摘要

Project Title. Blocking the immune response to Helper-dependent adenovirus vector for improved Hemophilia A gene therapy. Project Abstract. Hemophilia A (HA) is a common disorder of coagulation caused by deficiency of factor VIII (FVIII). The mainstay of treatment has been replacement therapy with recombinant human FVIII. However, because of high cost, access to therapy, and inhibitory antibody formation, patients continue to suffer from significant long-term morbidity and mortality. Our development of an optimized helper-dependent adenoviral gene vector (HDAds) system has enabled us to achieve long term expression of both secreted and intracellular transgenes without chronic toxicity and persistence of vector using both small and large animal models. However, acute toxicity remains an obstacle to clinical translation. To overcome this, we propose to develop immune suppressive HDAds expressing SOCS1 and/or coding TLR9 inhibitor sequences. However, because of the great redundancy of the innate immune system, we propose to develop adjunctive therapy in the form of hemofiltration that has already to be clinically-beneficial to remove the acute immune components in the context of sepsis. We will combine hemofiltration with improved immunosuppressive HDAds in safety studies in nonhuman primates. Ultimately, we will apply this approach to the preclinical treatment of FVIII deficiency in murine and canine HA . To address the potential adaptive immune response to FVIII therapy, we will co-express von Willebrand Factor (vWF) with FVIII. With these studies, we will address three important questions in genetic therapy for hemophilia A i) Can we decrease the innate immune response to HDAds? ii) Can we improve the efficacy of FVIII expression in HA model? iii) Can we decrease the innate immune response in nonhuman primate model with adjunctive hemofiltration? The overall goal of this application is to establish the safe and effective HA gene therapy with helper-dependent adenoviral vectors (HDAds) combined with hemofiltration that can be readily translated in the clinical arena for future clinical trials. During this mentored phase (K99), I will improve the therapeutic index of HDAd for HA therapy by combining cell autonomous immune suppression of the innate immune response, physical clearance of non-cell autonomous humoral factors, and stabilization factor of FVIII,. The mentored phase (K99) will occur at Baylor College of Medicine under the guidance of Dr. Brendan Lee. In the subsequent independent investigator phase (R00), I will apply this hybrid HDAds to canine HA in preparation for clinical studies. I will also evaluate the therapeutic effect of hemofiltration-assisted hybrid HDAds injection in nonhuman primates.

项目名称。阻断对辅助依赖性腺病毒载体的免疫反应以改善血友病 A 基因治疗。项目摘要。 A 型血友病 (HA) 是由因子 VIII (FVIII) 缺乏引起的常见凝血障碍。主要治疗方法是重组人 FVIII 替代疗法。然而，由于费用高昂、治疗的可及性和抑制性抗体的形成，患者继续遭受痛苦显着的长期发病率和死亡率。我们开发了一个优化的依赖助手腺病毒基因载体（HDAds）系统使我们能够实现两种分泌物的长期表达和细胞内转基因，使用小载体和大载体，没有慢性毒性和持久性动物模型。然而，急性毒性仍然是临床转化的障碍。为了克服这个问题，我们提议开发表达 SOCS1 和/或编码 TLR9 抑制剂的免疫抑制 HDAd 序列。然而，由于先天免疫系统存在大量冗余，我们建议开发血液滤过形式的辅助治疗，该治疗已经在临床上有益于去除脓毒症中的急性免疫成分。我们将把血液滤过与在非人类灵长类动物的安全性研究中改进了免疫抑制 HDAd。最终，我们将申请这种方法可用于鼠和犬 HA 中 FVIII 缺乏症的临床前治疗。为了解决对 FVIII 治疗的潜在适应性免疫反应，我们将共同表达冯·维勒布兰德因子 (vWF) 与FVIII。通过这些研究，我们将解决基因治疗中的三个重要问题血友病 A i) 我们可以减少对 HDAd 的先天免疫反应吗？ ii) 我们能否改进 HA 模型中 FVIII 表达的功效？ iii) 我们能否降低先天免疫反应具有辅助血液滤过的非人类灵长类动物模型？该应用程序的总体目标是利用辅助依赖性腺病毒载体 (HDAds) 建立安全有效的 HA 基因治疗与血液滤过相结合，可以很容易地转化为临床领域用于未来的临床试验。在这个指导阶段（K99），我将通过以下方式提高 HDAd 对 HA 治疗的治疗指数：结合细胞自主免疫抑制先天免疫反应、物理清除非细胞自主体液因子和FVIII稳定因子。指导阶段（K99）将在 Brendan Lee 博士的指导下，在贝勒医学院进行。在随后的独立调查员阶段 (R00)，我将把这种混合 HDAd 应用于犬 HA，为临床研究。我还将评估血液滤过辅助混合HDAds的治疗效果对非人类灵长类动物进行注射。