Advancing liver gene therapy: Enhanced transduction with GalNac-bioconjugated rAAV capsids

This study explores a novel strategy to enhance liver-targeted gene delivery, crucial for treating metabolic disorders. While AAV-based gene therapy holds promise, high vector doses raise safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. Optimizing capsids to improve hepatocyte transduction efficiency is key to reducing these risks. We employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), highly expressed on hepatocytes. Covalent attachment of GalNAc-derived ligands to rAAV2 capsids significantly improved in vivo liver transduction, increasing GFP expression up to threefold. Immunohistochemical co-labeling confirmed exclusive transgene expression in hepatocytes,ensuring specificity. These findings highlight bioconjugation as a promising approach to enhance liver gene therapy while improving safety by lowering vector doses and off-target effects.

About research
2025, 189, 118300
Pierre-Alban Lalys, Audrey Bourdon, Mohammed Bouzelha, Dimitri Alvarez-Dorta, Karine Pavageau, Tiphaine Girard, Roxane Peumery, Zakaria Bouchouireb, Maia Marchand, Anthony Mellet, Nicolas Jaulin, Mireille Ledevin, Olivia Terceve, Sébastien Depienne, Mickäel Guilbaud, Mikäel Croyal, Sébastien G. Gouin, Benoit Roubinet, Ludovic Landemarre, Oumeya Adjali, Eduard Ayuso, Thibaut Larcher, Caroline Le Guiner, Mathieu Mével, David Deniaud