Document Detail


Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins.
MedLine Citation:
PMID:  22850678     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gene therapy vectors based on the adeno-associated virus (AAV) are extremely efficient for gene transfer into post-mitotic cells of heart, muscle, brain, and retina. The reason for their exquisite tropism for these cells has long remained elusive. Here, we show that upon terminal differentiation, cardiac and skeletal myocytes downregulate proteins of the DNA damage response (DDR) and that this markedly induces permissivity to AAV transduction. We observed that expression of members of the MRN complex (Mre11, Rad50, Nbs1), which bind the incoming AAV genomes, faded in cardiomyocytes at ~2 weeks after birth, as well as upon myoblast differentiation in vitro; in both cases, withdrawal of the cells from the cell cycle coincided with increased AAV permissivity. Treatment of proliferating cells with short-interfering RNAs (siRNAs) against the MRN proteins, or with microRNA-24, which is normally upregulated upon terminal differentiation and negatively controls the Nbs1 levels, significantly increased permissivity to AAV transduction. Consistently, delivery of these small RNAs to the juvenile liver concomitant with AAV markedly improved in vivo hepatocyte transduction. Collectively, these findings support the conclusion that cellular DDR proteins inhibit AAV transduction and that terminal cell differentiation relieves this restriction.
Authors:
Jasmina Lovric; Miguel Mano; Lorena Zentilin; Ana Eulalio; Serena Zacchigna; Mauro Giacca
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-31
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  20     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-07     Completed Date:  2013-04-11     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2087-97     Citation Subset:  IM    
Affiliation:
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics,  metabolism
Animals
Cell Cycle
Cell Cycle Proteins / genetics,  metabolism
Cell Differentiation*
Cell Proliferation
DNA Damage
DNA Repair Enzymes / genetics,  metabolism
DNA-Binding Proteins / genetics,  metabolism
Dependovirus / genetics*
Down-Regulation
Gene Expression Regulation, Developmental*
Gene Knockdown Techniques
HeLa Cells
Heart / growth & development
Humans
Liver / metabolism,  virology
Mice
MicroRNAs / genetics,  metabolism
Muscle Fibers, Skeletal / physiology*,  virology
Myocytes, Cardiac / physiology*,  virology
Nuclear Proteins / genetics,  metabolism
RNA, Small Interfering / genetics
Rats
Transduction, Genetic*
beta-Galactosidase / biosynthesis,  genetics
Grant Support
ID/Acronym/Agency:
GGP11068//Telethon
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/MicroRNAs; 0/Mirn24 microRNA, mouse; 0/Mre11a protein, mouse; 0/Nijmegen breakage syndrome 1 protein, mouse; 0/Nuclear Proteins; 0/RNA, Small Interfering; 0/Rad50 protein, mouse; EC 3.2.1.23/beta-Galactosidase; EC 6.5.1.-/DNA Repair Enzymes
Comments/Corrections

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