Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids

Abstract

This study investigates novel approaches to improve targeted gene delivery to the liver, a crucial organ for metabolic processes that faces vulnerabilities from various pathologies. Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for liver targeting, with numerous investigational avenues. However, administration of high doses of AAV vectors present safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. To address this, substantial efforts are underway to engineer optimized capsids to enhance the efficiency and specificity of recombinant AAV (rAAV) targeting hepatocytes, aiming to reduce required dosages. In this study, we employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), a C-type lectin abundantly expressed at the surface of hepatocyte membranes. We demonstrated that covalently attaching carbohydrates derived from GalNAc (a known ASGPR ligand) to lysine amino-acids on the rAAV2 capsid significantly enhanced in vivo liver transduction efficiency in mice. These optimized vectors present a promising avenue for the treatment of a spectrum of liver diseases, providing an alternative solution within the framework of liver gene therapy.