Vigilant vectors: adeno-associated virus with a biosensor to switch on amplified therapeutic genes in specific tissues in life-threatening diseases.
There are many life-threatening and chronic diseases in which physiological signals could be used to switch on therapeutic protective genes. We are developing a gene therapy approach in which a systemically injected "vigilant vector" waits for these signals and switches on genes to protect specific tissues with high amplification. The concept of a vigilant vector requires four components. The first component is a safe and stable vector that can be administered by systemic injection and express transgenes in a particular organ or tissue. The adeno-associated virus vector is safe and stable for this purpose. The second component is a reversible gene switch which is a biosensor that can detect certain physiological signals. We are developing a hypoxia switch, based on the oxygen-dependent degradation domain of hypoxia-inducible factor. The third component is a tissue-specific promoter, and we have used the myosin light-chain-2V promoter for specific expression in the heart. The fourth component is an amplification system. For this we have developed a double-plasmid/vector system based on the yeast GAL4 and human transcriptional activator p65 to produce a transactivating fusion protein that binds to a GAL4 activation sequence in an activating plasmid that then expresses high levels of cardioprotective genes.
Tang
Yi
Y
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Box 100274, Gainesville, FL 32610-0274, USA.
Schmitt-Ott
Kai
K
Qian
Keping
K
Kagiyama
Shuntaro
S
Phillips
M Ian
MI
D000208:Acute Disease / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015374:Biosensing Techniques / Q000379:methods*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000628:therapy; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000821:virology; D018994:Myosin Light Chains / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009928:Organ Specificity; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013539:Simian virus 40 / Q000235:genetics; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018994:Myosin Light Chains; D009687:Nuclear Proteins; D014157:Transcription Factors