title: Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. We used recombinant adenoassociated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene (ABCD1) to mouse central nervous system (CNS). In vitro, efficient delivery of ABCD1 gene was achieved in primary mixed brain glial cells from Abcd1-/- mice as well as X-ALD patient fibroblasts. Importantly, human ABCD1 localized to the peroxisome, and AAV-ABCD1 transduction showed a dose-dependent effect in reducing VLCFA. In vivo, AAV9-ABCD1 was delivered to Abcd1-/- mouse CNS by either stereotactic intracerebroventricular (ICV) or intravenous (IV) injections. Astrocytes, microglia and neurons were the major target cell types following ICV injection, while IV injection also delivered to microvascular endothelial cells and oligodendrocytes. IV injection also yielded high transduction of the adrenal gland. Importantly, IV injection of AAV9-ABCD1 reduced VLCFA in mouse brain and spinal cord. We conclude that AAV9-mediated ABCD1 gene transfer is able to reach target cells in the nervous system and adrenal gland as well as reduce VLCFA in culture and a mouse model of X-ALD.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Dakai
authors.initials: D
authors.lastname: Mu
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Peroxisome Disease Lab, Hugo W Moser Research Institute, Baltimore, Maryland, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Moser
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Musolino
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: JiaQian
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address: feichler@partners.org.
authors.forename: Florian S
authors.initials: FS
authors.lastname: Eichler
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000628:therapy; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism; D021381:Protein Transport; D065288:Serogroup; D014161:Transduction, Genetic; D000094765:Glutathione Peroxidase GPX1
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1