Immunopharmacology of FVIII Bioengineering and Gene Therapy

FVIII 生物工程和基因治疗的免疫药理学

• 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
• 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

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生物工程和基因治疗的免疫药理学 摘要 针对人类第VIII因子的抑制性抗体的发展仍然是最有意义的临床研究。 与治疗血友病A相关的并发症，是基因治疗方法的关键障碍。 因此，提高了对与有希望的肝脏导向相关的免疫学和药理学的理解 腺相关病毒载体和造血干细胞介导的慢病毒载体基因 治疗策略是必要的。本U54申请的项目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。建议的研究是设计的 分析生物工程重组输液产品的分子组成和免疫反应性 以及肝脏导向的AAV和HSC导向的LV基因疗法衍生的FVIII，II)确定关键设计 肝源性AAV-FVIII基因免疫原性和抑制物放射潜能的相关参数 治疗和III)评估非遗传毒性HSC的免疫原性和抑制物根除潜力 LV基因治疗方案。这些研究将利用现有的FVIII、糖组学、结构生物学、 免疫学和基因治疗的专业知识以及各种最先进的技术，包括我们最近的 在电子密码子优化、合成启动子工程和祖先序列重建中描述 技术，以提高目前的理解和更好地评估基因治疗的总体潜力 解决所有血友病A患者群体，包括那些使用FVIII抑制剂的患者。