Document Detail


Sexually dimorphic patterns of episomal rAAV genome persistence in the adult mouse liver and correlation with hepatocellular proliferation.
MedLine Citation:
PMID:  19568224     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recombinant adeno-associated virus vectors (rAAVs) show exceptional promise for liver-targeted gene therapy, with phenotype correction in small and large animal disease models being reported with increasing frequency. Success in humans, however, remains a considerable challenge that demands greater understanding of host-vector interactions, notably those governing the efficiency of initial gene transfer and subsequent long-term persistence of gene expression. In this study, we examined long-term enhanced green fluorescent protein (eGFP) expression and vector genome persistence in the mouse liver after rAAV2/8-mediated gene transfer in early adulthood. Two intriguing findings emerged of considerable scientific and clinical interest. First, adult female and male mice showed distinctly different patterns of persistence of eGFP expression across the hepatic lobule after exhibiting similar patterns initially. Female mice retained a predominantly perivenous pattern of expression, whereas male mice underwent inversion of this pattern with preferential loss of perivenous expression and relative retention of periportal expression. Second, these changing patterns of expression correlated with sexually dimorphic patterns of genome persistence that appear linked both spatially and temporally to underlying hepatocellular proliferation. Observation of the equivalent phenomenon in man could have significant implications for the long-term therapeutic efficacy of rAAV-mediated gene transfer, particularly in the context of correction of liver functions showing metabolic zonation.
Authors:
Allison P Dane; Sharon C Cunningham; Nicole S Graf; Ian E Alexander
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-30
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  17     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-11-10     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1548-54     Citation Subset:  IM    
Affiliation:
Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation
Dependovirus / genetics*
Female
Genetic Therapy
Genetic Vectors / genetics*
Genome, Viral / genetics
Green Fluorescent Proteins / genetics,  metabolism
Humans
Immunohistochemistry
Liver / cytology*,  metabolism*
Male
Mice
Sex Factors
Chemical
Reg. No./Substance:
0/enhanced green fluorescent protein; 147336-22-9/Green Fluorescent Proteins
Comments/Corrections

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