Mitigating the Immunogenicity of AAV-Mediated Gene Therapy with an Immunosuppressive Phosphoserine-Containing Zwitterionic Peptide

Although recombinant adeno-associated viruses (AAVs) are considered low immunogenic and safe for gene delivery, the immunogenicity of capsids still represents a major obstacle to the readministration of AAV vectors. Here, we design an immunosup-pressive zwitterionic phosphoserine (PS)-containing polypeptide to induce AAV-specific immune tolerance and eradicate the immuno-logical response. AAVs modified with the zwitterionic PS polypeptide maintain their transduction activity and tissue tropism but suppress the induction of AAV-specific antibodies. In a hemophilia A mouse model (FVIII knockout mice), the readministration of zwitterionic PS polypeptide-modified AAV8-FVIII vectors successfully evades im-munological response, corrects blood FVIII levels, and stops blood loss in tail-bleeding experiments. This potent and safe technology mimics the natural tolerance of apoptotic cells and controls the immunosuppressive, zwitterionic, and degradable polypeptide precisely, reducing the concern of toxicities upon readministrations. This work presents a new concept and a platform of engineered viral vectors by chemically linking immunosuppressive materials to AAV vectors, enabling the readministration of AAV vectors while maintaining their transduction efficiency to a considerable degree.

Automated summary

This study presents a new approach to enhance immune tolerance and reduce immunological response to AAV vectors by using an immunosuppressive zwitterionic polypeptide. The modified AAV vectors maintain their transduction efficiency while avoiding the production of AAV-specific antibodies.