A Self-inactivating γ-Retroviral Vector Reduces Manifestations of Mucopolysaccharidosis I in Mice
| Autor: | Kevin K. Ohlemiller, Attila Kovacs, Li He, Douglas M. Tollefsen, Jason A. Metcalf, Axel Schambach, Xiucui Ma, Susan Wu, Bruce Linders, Katherine P. Ponder, Mark Bigg |
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| Rok vydání: | 2010 |
| Předmět: |
viruses
Mucopolysaccharidosis I Genetic Vectors Biology Viral vector Glycosaminoglycan Insertional mutagenesis 03 medical and health sciences Transduction (genetics) Iduronidase Mice 0302 clinical medicine Dogs Drug Discovery Lysosomal storage disease medicine Genetics Animals Humans Promoter Regions Genetic Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Terminal Repeat Sequences Original Articles Genetic Therapy medicine.disease Long terminal repeat 3. Good health Retroviridae Marmota alpha 1-Antitrypsin Immunology Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Molecular Therapy. 18(2):334-342 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2009.236 |
| Popis: | Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficiency in alpha-L-iduronidase (IDUA) that results in accumulation of glycosaminoglycans (GAGs) throughout the body, causing numerous clinical defects. Intravenous administration of a gamma-retroviral vector (gamma-RV) with an intact long terminal repeat (LTR) reduced the clinical manifestations of MPS I, but could cause insertional mutagenesis. Although self-inactivating (SIN) gamma-RVs in which the enhancer and promoter elements in the viral LTR are absent after transduction reduces this risk, such vectors could be less effective. This report demonstrates that intravenous (i.v.) injection of a SIN gamma-RV expressing canine IDUA from the liver-specific human alpha(1)-antitrypsin promoter into adult or newborn MPS I mice completely prevents biochemical abnormalities in several organs, and improved bone disease, vision, hearing, and aorta to a similar extent as was seen with administration of the LTR-intact vector to adults. Improvements were less profound than when using an LTR-intact gamma-RV in newborns, which likely reflects a lower level of transduction and expression for the SIN vector-transduced mice, and might be overcome by using a higher dose of SIN vector. A SIN gamma-RV vector ameliorates clinical manifestations of MPS I in mice and should be safer than an LTR-intact gamma-RV. |
| Databáze: | OpenAIRE |
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