Immunopharmacology of FVIII Bioengineering and Gene Therapy

FVIII 生物工程和基因治疗的免疫药理学

基本信息

批准号：
10406904
负责人：
Christopher Bradley Doering
金额：
$ 34.32万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406904
关键词：
Address Adult Animal Model Antibodies Antibody Response Autologous Benefits and Risks Biodistribution Biomedical Engineering Bioreactors CD34 gene Cell Culture System Cells Clinical Codon Nucleotides Collection Complication Data Development Engineering Exposure to F8 gene Factor VIII Family suidae Gene Transduction Agent Genetic Goals Hematopoietic Hematopoietic System Hematopoietic stem cells Hemophilia A Hepatocyte Human Hybrids Immune Immune Tolerance Immune response Immune system Immunity Immunize Immunobiology Immunology Infusion procedures Investigation Knowledge Lentivirus Vector Light Liver Metabolism Methods Modification Molecular Mus Neoadjuvant Therapy Outcome Patients Pharmacology Plasma Population Primary Cell Cultures Protocols documentation Recombinants Recording of previous events Risk Safety System Technology Testing Therapeutic Transgenes Variant Viral adeno-associated viral vector clinical development clinically relevant cytokine design gene therapy gene therapy clinical trial immunogenicity immunopharmacology immunoregulation improved in silico in vivo inhibitor knowledge base metabolic abnormality assessment mouse model novel patient population pre-clinical promoter reconstruction structural biology therapeutic evaluation

Address Adult Animal Model Antibodies Antibody Response Autologous Benefits and Risks Biodistribution Biomedical Engineering Bioreactors CD34 gene Cell Culture System Cells Clinical Codon Nucleotides Collection Complication Data Development Engineering Exposure to F8 gene Factor VIII Family suidae Gene Transduction Agent Genetic Goals Hematopoietic Hematopoietic System Hematopoietic stem cells Hemophilia A Hepatocyte Human Hybrids Immune Immune Tolerance Immune response Immune system Immunity Immunize Immunobiology Immunology Infusion procedures Investigation Knowledge Lentivirus Vector Light Liver Metabolism Methods Modification Molecular Mus Neoadjuvant Therapy Outcome Patients Pharmacology Plasma Population Primary Cell Cultures Protocols documentation Recombinants Recording of previous events Risk Safety System Technology Testing Therapeutic Transgenes Variant Viral adeno-associated viral vector clinical development clinically relevant cytokine design gene therapy gene therapy clinical trial immunogenicity immunopharmacology immunoregulation improved in silico in vivo inhibitor knowledge base metabolic abnormality assessment mouse model novel patient population pre-clinical promoter reconstruction structural biology therapeutic evaluation

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项目摘要

Project 3: Immunopharmacology of FVIII Bioengineering and Gene Therapy Summary The development of inhibitory antibodies directed against human factor VIII remains the most significant clinical complication associated with the treatment of hemophilia A and is a critical barrier to gene therapy approaches. Therefore, improved understanding of the immunology and pharmacology related to promising liver-directed adeno-associated viral (AAV) vector and hematopoietic stem cell (HSC)-directed lentiviral vector (LV) gene therapy strategies is needed. The studies proposed in Project 3 of this U54 application are designed to advance our knowledge of fVIII immunobiology in the context of these gene therapies. The proposed studies are designed to i) analyze the molecular composition and immune reactivity of bioengineered recombinant infusion products as well as liver-directed AAV and HSC-directed LV gene therapy derived fVIII, ii) identify critical design parameters associated with immunogenicity and inhibitor eradiation potential of liver-directed AAV-fVIII gene therapy and iii) evaluate the immunogenicity and inhibitor eradicating potential of non-genotoxic HSC-directed LV gene therapy protocols. These studies will take advantage of available fVIII, glycomics, structural biology, immunology and gene therapy expertise as well as diverse state-of-the-art technologies, including our recently described in silico codon-optimization, synthetic promoter engineering and ancestral sequence reconstruction technology, to improve the current understanding and better assess the overall potential for gene therapy to address all hemophilia A patient populations including those with fVIII inhibitors.

项目3：FVIII生物工程和基因疗法的免疫药理学概括针对人因子VIII的抑制性抗体的发展仍然是最重要的临床与血友病A治疗相关的并发症是基因治疗方法的关键障碍。因此，对与有前途的肝脏指导有关的免疫学和药理学的了解得到了改善腺相关病毒（AAV）载体和造血干细胞（HSC）指导的慢病毒载体（LV）基因需要治疗策略。该U54应用程序3中提出的研究旨在推进在这些基因疗法的背景下，我们对FVIII免疫生物学的了解。拟议的研究是设计的 i）分析生物工程重组产品的分子组成和免疫反应性以及肝导向的AAV和HSC定向的LV基因疗法衍生的FVIII，ii）确定关键设计与肝脏定向AAV-FVIII基因的免疫原性和抑制剂消除潜力相关的参数治疗和iii）评估非生物毒性HSC指导的免疫原性和抑制剂消除潜力 LV基因治疗方案。这些研究将利用可用的FVIII，糖基质，结构生物学，免疫学和基因疗法专业知识以及各种最先进的技术，包括我们最近的在硅密码子优化，合成启动子工程和祖先序列重建中描述技术，以提高当前的理解并更好地评估基因治疗的总体潜力解决所有血友病的患者人群，包括患有FVIII抑制剂的患者。