| Alpharetroviral Vector-mediated Gene Therapy for X-CGD: Functional Correction and Lack of Aberrant Splicing. | |
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MedLine Citation:
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PMID: 23207695 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model to evaluate the potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy of monogenic diseases. Therefore, we combined the alpharetroviral vector backbone with the elongation factor-1α short promoter, both considered to possess a low genotoxic profile, to drive transgene (gp91(phox)) expression. Following efficient transduction transgene expression was sustained and provided functional correction of the CGD phenotype in a cell line model at low vector copy number. Further analysis in a murine X-CGD transplantation model revealed gene-marking of bone marrow cells and oxidase positive granulocytes in peripheral blood. Transduction of human X-CGD CD34+ cells provided functional correction up to wild-type levels and long-term expression upon transplantation into a humanized mouse model. In contrast to lentiviral vectors, no aberrantly spliced transcripts containing cellular exons fused to alpharetroviral sequences were found in transduced cells, implying that the safety profile of alpharetroviral vectors may extend beyond their neutral integration profile. Taken together, this highlights the potential of this SIN alpharetroviral system as a platform for new candidate vectors for future gene therapy of hematopoietic disorders.Molecular Therapy (2012); doi:10.1038/mt.2012.249. |
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Authors:
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Kerstin B Kaufmann; Christian Brendel; Julia D Suerth; Uta Mueller-Kuller; Linping Chen-Wichmann; Joachim Schwäble; Shweta Pahujani; Hana Kunkel; Axel Schambach; Christopher Baum; Manuel Grez |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-12-04 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: - ISSN: 1525-0024 ISO Abbreviation: Mol. Ther. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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