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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.

降低工程AAV基因传递载体的免疫原性