Document Detail


Destabilizing domains mediate reversible transgene expression in the brain.
MedLine Citation:
PMID:  23029456     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Regulating transgene expression in vivo by delivering oral drugs has been a long-time goal for the gene therapy field. A novel gene regulating system based on targeted proteasomal degradation has been recently developed. The system is based on a destabilizing domain (DD) of the Escherichia coli dihydrofolate reductase (DHFR) that directs fused proteins to proteasomal destruction. Creating YFP proteins fused to destabilizing domains enabled TMP based induction of YFP expression in the brain, whereas omission of TMP resulted in loss of YFP expression. Moreover, induction of YFP expression was dose dependent and at higher TMP dosages, induced YFP reached levels comparable to expression of unregulated transgene., Transgene expression could be reversibly regulated using the DD system. Importantly, no adverse effects of TMP treatment or expression of DD-fusion proteins in the brain were observed. To show proof of concept that destabilizing domains derived from DHFR could be used with a biologically active molecule, DD were fused to GDNF, which is a potent neurotrophic factor of dopamine neurons. N-terminal placement of the DD resulted in TMP-regulated release of biologically active GDNF. Our findings suggest that TMP-regulated destabilizing domains can afford transgene regulation in the brain. The fact that GDNF could be regulated is very promising for developing future gene therapies (e.g. for Parkinson's disease) and should be further investigated.
Authors:
Khalid Tai; Luis Quintino; Christina Isaksson; Fredrik Gussing; Cecilia Lundberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-28
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-02-21     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e46269     Citation Subset:  IM    
Affiliation:
CNS Gene Therapy Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Infective Agents / pharmacology
Bacterial Proteins / genetics,  metabolism
Brain / drug effects*,  metabolism
Cell Line, Tumor
Escherichia coli / chemistry,  genetics
Female
Gene Expression*
Genetic Therapy
Genetic Vectors
Glial Cell Line-Derived Neurotrophic Factor / genetics*,  metabolism
Humans
Injections, Intraventricular
Lentivirus / genetics
Luminescent Proteins / genetics,  metabolism
Models, Animal
Molecular Targeted Therapy
Parkinson Disease / genetics,  metabolism,  therapy
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins / administration & dosage*,  genetics,  metabolism
Tetrahydrofolate Dehydrogenase / genetics*,  metabolism
Transgenes*
Trimethoprim / pharmacology
Chemical
Reg. No./Substance:
0/Anti-Infective Agents; 0/Bacterial Proteins; 0/GDNF protein, human; 0/Glial Cell Line-Derived Neurotrophic Factor; 0/Luminescent Proteins; 0/Recombinant Fusion Proteins; 0/yellow fluorescent protein, Bacteria; 738-70-5/Trimethoprim; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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