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

基本信息

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
项目类别：
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

项目摘要

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.

减轻工程化 AAV 基因递送载体的免疫原性通过生物材料驱动的免疫抑制项目概要重组腺相关病毒（AAV）载体介导的基因传递有望用于各种慢性病和遗传病。尽管迄今为止取得了巨大的临床成果，AAV 载体基因由于其耐用性，交付受到限制。单次 AAV 给药可持续数月至数月多年的基因表达高于治疗水平。然而，许多遗传性疾病需要终生治疗以避免不可逆的组织损伤。因此，重新施用 AAV 的能力对于随着时间的推移实现持续的治疗效果。尽管 AAV 被认为具有低免疫原性与其他病毒载体相比，衣壳的免疫原性仍然是一个主要因素 AAV 载体重新施用的障碍。为了应对这些挑战，我们采用内源性免疫耐受结构，来自天然磷脂酰丝氨酸脂质的磷酸丝氨酸 (PS)，作为免疫抑制部分，能够 AAV 载体的重新施用。避免由于内在的作用而导致功效损失或循环短路由于原生 PS 结构的负电荷，我们建议将 PS 结构设计成明确定义的具有总两性/中性电荷和高PS的免疫抑制可降解PS肽材料密度并将其与 AAV 衣壳缀合，从而使修饰后的基因载体能够重新施用能力。两个具体目标是 (a) 含 PS 两性离子的制备和表征肽修饰的 AAV； (b) 体内免疫耐受和正常情况下基因传递的多剂量研究和 FIX 缺陷小鼠。拟议的工作将开发一种生物材料驱动的、具有免疫抑制功能的两性离子基于PS肽的病毒载体工程平台，实现AAV载体的再给药保持其转导效率。该项目的支持将启动一个用于 AAV 介导的基因传递领域的可翻译生物材料技术。此次活动的成功项目将推进当前基于 AAV 的基因治疗，并为患者提供临床益处。