Document Detail

Alpharetroviral vector-mediated gene therapy for X-CGD: functional correction and lack of aberrant splicing.
MedLine Citation:
PMID:  23207695     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-04
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-10-22     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  648-61     Citation Subset:  IM    
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MeSH Terms
Alpharetrovirus / genetics*
Bone Marrow Cells
Cell Line, Tumor
DNA Copy Number Variations
Disease Models, Animal
Genetic Therapy / methods*
Genetic Vectors*
Granulomatous Disease, Chronic / genetics,  therapy*
Membrane Glycoproteins / genetics,  metabolism
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase / genetics,  metabolism
RNA Splicing*
Reverse Transcriptase Polymerase Chain Reaction
Transduction, Genetic
Reg. No./Substance:
0/CYBB protein, human; 0/Membrane Glycoproteins; EC Oxidase

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