title: Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice.
abstract: Mucopolysaccharidosis (MPS) IIIA is a neuropathic lysosomal storage disease caused by deficiency in N-sulfoglucosamine sulfohydrolase (SGSH). Genome-wide gene expression microarrays in MPS IIIA mice detected broad molecular abnormalities (greater than or equal to twofold, false discovery rate ≤10) in numerous transcripts (314) in the brain and blood (397). Importantly, 22 dysregulated blood transcripts are known to be enriched in the brain and linked to broad neuronal functions. To target the root cause, we used a self-complementary AAVrh74 vector to deliver the human SGSH gene into 4-6 weeks old MPS IIIA mice by an intravenous injection. The treatment resulted in global central nervous system (CNS) and widespread somatic restoration of SGSH activity, clearance of CNS and somatic glycosaminoglycan storage, improved behavior performance, and significantly extended survival. The scAAVrh74-hSGSH treatment also led to the correction of the majority of the transcriptional abnormalities in the brain (95.9%) and blood (97.7%), of which 182 and 290 transcripts were normalized in the brain and blood, respectively. These results demonstrate that a single systemic scAAVrh74-hSGSH delivery mediated efficient restoration of SGSH activity and resulted in a near complete correction of MPS IIIA molecular pathology. This study also demonstrates that blood transcriptional profiles reflect the biopathological status of MPS IIIA, and also respond well to effective treatments.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: F Jason
authors.initials: FJ
authors.lastname: Duncan
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Bartholomew J
authors.initials: BJ
authors.lastname: Naughton
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Zaraspe
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Darren A
authors.initials: DA
authors.lastname: Murrey
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Meadows
authors.affiliation: 1] Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kelly Reed
authors.initials: KR
authors.lastname: Clark
authors.affiliation: Biomedical Genetics Core, Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Newsom
authors.affiliation: 1] Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA [2] Biomedical Genetics Core, Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: White
authors.affiliation: 1] Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
authors.affiliation: 1] Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: McCarty
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009084:Mucopolysaccharidosis III / Q000628:therapy*
chemical_list: D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase