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

点击翻译按钮获取中文摘要

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.