title: Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction.
abstract: Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 1011vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 × 1010vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA-mediated tolerogenic gene therapy in Pompe disease mice.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Han
authors.affiliation: Genethon and INSERM U951, 91002 Evry, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronzitti
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Arnson
authors.affiliation: Genethon and INSERM U951, 91002 Evry, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Leborgne
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.affiliation: Genethon and INSERM U951, 91002 Evry, France; University Pierre and Marie Curie - Paris 6, 75005 Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Dwight
authors.initials: D
authors.lastname: Koeberl
keywords: acid maltase; acid α-glucosidase; adeno-associated virus; gene therapy; glycogen storage disease type II; immune tolerance induction