Polymer-based coating of adeno-associated viral particles as a new strategy to evade immune response for DMD treatment

Abstract

Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by mutations in the dystrophin gene, leading to progressive muscle degeneration. Gene therapy using adeno-associated virus (AAV) vectors holds potential for treating DMD, but challenges such as immune responses and limited efficacy hinder its success. This study proposes a novel approach to improve AAV-based gene therapy by coating AAV vectors with a modified poly(β-amino ester) (pBAE) polymer featuring an NHS-activated acid moiety. The pBAE coating increases the positive surface charge of AAV particles, enhancing their transduction efficiency in muscle cells and reducing interactions with neutralizing antibodies. In vitro and in vivo studies demonstrate that pBAE-coated AAVs exhibit improved transduction efficiency, stability under physiological conditions, and targeted muscle tissue expression. Additionally, the coating protects AAV from neutralizing antibodies and reduces their production, addressing significant limitations in AAV-based gene therapy. This strategy represents a promising advancement in enhancing the efficacy and safety of gene therapy for DMD and potentially other genetic disorders.