IgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice.

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 (IdeSop). When incubated in vitro, IdeSop was shown to completely cleave human and rabbit IgGs within 6 h. To test IdeSop 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. IdeSop-Ab-cleavage was shown to be dose-dependent. An IV IdeSop 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-hSGSHop vector (5 × 1013vg/kg) at 24 h post IdeSop treatment led to transduction as effective in αAAV9-Abs+ MPS IIIA mice, as in αAAV9-Abs-negative controls. We believe that transient IdeSop 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.

Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

No treatment is available to address the unmet needs of mucopolysaccharidosis (MPS) IIIA patients. Targeting the root cause, we developed a new self-complementary adeno-associated virus 9 (scAAV9) vector to deliver the human N-sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a miniature cytomegalovirus (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single intravenous (i.v.) infusion into MPS IIIA mice at different ages. The vector treatments resulted in rapid and long-term expression of functional recombinant SGSH (rSGSH) enzyme and elimination of lysosomal storage pathology throughout the CNS and periphery in all tested animals. Importantly, MPS IIIA mice treated with the vector at up to 6 months of age showed significantly improved behavior performance in a hidden task in the Morris water maze, as well as extended lifespan, with most of the animals surviving within the normal range, indicating that the vector treatment can prevent and reverse MPS IIIA disease progression. Notably, 2.5 × 1012 vector genomes (vg)/kg was functionally effective. Furthermore, the vector treatment did not lead to detectable systemic toxicity or adverse events in MPS IIIA mice. These data demonstrate the development of a safe and effective new gene therapy product for treating MPS IIIA, which further support the extended clinical relevance of platform recombinant AAV9 (rAAV9 gene delivery for treating broad neurogenetic diseases.