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