The widespread pre-existing αAAV-Abs in humans pose a critical challenge in translation of AAV gene therapy. The IgG degrading enzyme of Streptococci (IdeS) is demonstrated to specifically cleave IgG of humans and other species (not mouse). This study developed a modified new modified IdeS protein product (IdeS). When incubated in vitro, IdeS was shown to completely cleave human and rabbit IgGs within 6 h. To test IdeS in a disease setting, we established a rabbitized αAAV9-Ab mouse by an IV infusion of purified acute αAAV9-Ab rabbit IgG into MPS IIIA mice, resulting in serum αAAV9-IgG at 1:6,400 and αAAV9-nAbs at 1:800. IdeS-Ab-cleavage was shown to be dose-dependent. An IV IdeS infusion at the effective doses resulted in rapid IgG depletion and clearance of pre-existing αAAV9-IgG and αAAV9-nAbs in rabbitized αAAV9-Abs MPS IIIA mice. Importantly, an IV injection of a high dose AAV9-hSGSH vector (5 × 10vg/kg) at 24 h post IdeS treatment led to transduction as effective in αAAV9-Abs MPS IIIA mice, as in αAAV9-Abs-negative controls. We believe that transient IdeS administration may offer a great tool to address the pre-existing-αAAV-Abs for the translation of rAAV gene therapy to treat diseases in humans, making effective rAAV gene therapy available to all patients in need.