title: Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery.
abstract: Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in α-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-month-old MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital (NCH-RI), Columbus, OH 43205, USA; Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43202, USA. Electronic address: haiyan.fu@nationwidechildrens.org.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital (NCH-RI), Columbus, OH 43205, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Meadows
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital (NCH-RI), Columbus, OH 43205, USA.
authors.forename: Tierra
authors.initials: T
authors.lastname: Ware
authors.affiliation: Metabolon, Inc., Durham, NC 27713, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital (NCH-RI), Columbus, OH 43205, USA; Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43202, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: McCarty
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D016000:Cluster Analysis; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D009084:Mucopolysaccharidosis III / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D018377:Neurotransmitter Agents / Q000378:metabolism; D010641:Phenotype; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018377:Neurotransmitter Agents; C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase
keywords: AAV9; MPS IIIB; biomarkers; global metabolomics profiling; systemic gene delivery