Mitigating the Immunogenicity of Engineered Aav Gene Delivery Vectors by Biomaterial-Driven Immunosuppression

通过生物材料驱动的免疫抑制减轻工程化 Aav 基因递送载体的免疫原性

• 批准号: 10741139
• 负责人: SHAOYI JIANG
• 金额: $ 43.54万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741139
• 关键词: Address; Adopted; Antibodies; B-Lymphocytes; Biocompatible Materials; Blood; Capsid; Charge; Chemistry; Chronic Disease; Circulation; Clinical; DNA cassette; DNA delivery; Dependovirus; Development; Disease model; Dose; Engineering; Evaluation; FDA approved; Feedback; Flow Cytometry; Formulation; Gene Delivery; Gene Expression; Generations; Genes; Genetic Diseases; Hemorrhage; Hereditary Disease; Immune Tolerance; Immune response; Immunocompetent; Immunologic Tests; Immunosuppression; In Vitro; Knockout Mice; Length; Lipids; Liver; Luciferases; Mediating; Methods; Modeling; Monitor; Mus; Outcome; Outcome Study; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phase; Phosphatidylserines; Phosphoserine; Polymers; Preparation; Proteins; Recombinant adeno-associated virus (rAAV); Serotyping; Solid; Structure; T-Lymphocyte; Tail; Technology; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Viral Vector; Work; adeno-associated viral vector; chemical synthesis; delivery vehicle; density; drug efficacy; efficacy study; enzyme linked immunospot assay; experimental study; gene therapy; immunogenic; immunogenicity; in vivo; success; technology validation; transduction efficiency; vector

Mitigating the immunogenicity of engineered AAV gene delivery vectors by biomaterial-driven immunosuppression PROJECT SUMMARY Recombinant adeno-associated virus (AAV) vector-mediated gene delivery is promising for a variety of chronic and genetic diseases. Despite huge clinical outcomes to date, AAV vector gene delivery has been limited due to its durability. Single AAV administration can last from months to several years of gene expression above therapeutic levels. However, many inherited diseases require lifelong treatment to avoid irreversible tissue damage. Thus, the ability to re-administer AAV is crucial to achieving sustained therapeutic efficacy over time. Although AAVs are considered low immunogenic and safe as compared with other viral vectors, the immunogenicity of capsids still represents a major obstacle to the re-administration of AAV vectors. To address these challenges, we adopt an endogenous immune tolerant structure, phosphoserine (PS) from natural phosphatidylserine lipid, as an immunosuppressive moiety to enable the re-administration of AAV vectors. To avoid efficacy loss or short circulation due to the intrinsic negative charge of native PS structure, we propose to engineer the PS structure into a well-defined immunosuppressive degradable PS peptide material with overall zwitterion/neutral charge and high PS density and conjugate it to AAV capsids, thus enabling the modified gene vectors with re-administration capability. Two Specific Aims are (a) preparation and characterization of PS-containing zwitterionic peptide-modified AAVs; (b) in vivo immune tolerance and multi-dose study of gene delivery in normal and FIX-deficient mice. The proposed work will develop a biomaterial-driven, immunosuppression-enabling, zwitterionic PS peptide-based viral vector engineering platform, realizing the re-administration of AAV vectors while maintaining their transduction efficiency. Support of this project will initiate the development of a translatable biomaterial technology for the field of AAV-mediated gene delivery. The success of this project will advance the current AAV-based gene therapy and provide clinical benefits to patients.

缓解工程AAV基因递送向量的免疫原性 通过生物材料驱动的免疫抑制 项目摘要 重组腺相关病毒（AAV）载体介导的基因输送有望成为A 多种慢性和遗传疾病。尽管迄今为止的临床结果很大，AAV矢量基因 由于其耐用性，交付受到限制。单一AAV管理可以持续几个月到几个月 高于治疗水平的基因表达年。但是，许多继承疾病需要终身 治疗以避免不可逆的组织损伤。因此，重新管理AAV的能力对 随着时间的流逝，达到持续的治疗功效。尽管AAV被认为是低免疫原性的 与其他病毒载体相比，安全性安全，衣壳的免疫原性仍然代表主要 AAV向量重新管理的障碍。 为了应对这些挑战，我们采用内源性免疫耐受结构， 自然磷脂酰丝氨酸脂质的磷酸盐（PS）作为免疫抑制部分以启用 AAV向量的重新管理。避免由于固有的效果丧失或短期循环 天然PS结构的负电荷，我们建议将PS结构设计为明确的 具有整体zwitter/中性电荷和高PS的免疫抑制作用可降解的PS肽材料 密度并将其缀合至AAV capsids，从而使改良的基因向量具有重新管理 能力。两个具体的目的是（a）含PS的zwitterionic的准备和表征 肽修饰的AAV； （b）正常的基因递送的体内免疫耐受性和多剂量研究 和固定缺乏的小鼠。 拟议的工作将开发出生物材料驱动的，免疫抑制的Zwitterionic 基于PS肽的病毒矢量工程平台，实现了AAV矢量的重新管理 保持其转导效率。该项目的支持将启动 AAV介导的基因输送领域的可翻译生物材料技术。这个成功 项目将推进当前基于AAV的基因疗法，并为患者提供临床益处。