Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy
| Autor: | Ann B. Moser, Florian Eichler, Xandra O. Breakefield, Patricia L. Musolino, Dakai Mu, Casey A. Maguire, Jia Qian Ren, Yi Gong, Shilpa Prabhakar |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Nervous system Genetic enhancement Gene Expression ATP Binding Cassette Transporter Subfamily D Member 1 Mice Glutathione Peroxidase GPX1 0302 clinical medicine Genes Reporter Transduction Genetic Drug Discovery Gene expression Adrenoleukodystrophy Cells Cultured Mice Knockout 0303 health sciences Microglia Fatty Acids Brain Dependovirus 3. Good health Protein Transport medicine.anatomical_structure Molecular Medicine Neuroglia Original Article Genetic Vectors Central nervous system Biology Serogroup 03 medical and health sciences Cell Line Tumor Genetics medicine Animals Humans Molecular Biology 030304 developmental biology Pharmacology Glutathione Peroxidase Genetic Therapy Fibroblasts medicine.disease Virology Molecular biology Disease Models Animal Cell culture ATP-Binding Cassette Transporters 030217 neurology & neurosurgery |
| Zdroj: | Molecular Therapy. 23:824-834 |
| ISSN: | 1525-0016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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