Effect of heart ischemia and administration route on biodistribution and transduction efficiency of AAV9 vectors
| Autor: | Olalla Iglesias-García, Africa Vales, Adrián Ruiz-Villalba, Gloria González-Aseguinolaza, Gloria Abizanda, Beatriz Pelacho, Juan R. Rodriguez-Madoz, Paula García-Olloqui, Laura Pilar Aguado-Alvaro, Cristina Olagüe, Eduardo Larequi, Marianna Di Scala, Felipe Prosper |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Heart disease Transgene Genetic Vectors Green Fluorescent Proteins 0206 medical engineering Myocardial Infarction Myocardial Ischemia Biomedical Engineering Ischemia Medicine (miscellaneous) Genome Viral 02 engineering and technology Pharmacology Biology Biomaterials Mice 03 medical and health sciences Transduction (genetics) Peptide Elongation Factor 1 Troponin T Transduction Genetic Gene expression medicine Animals Humans Myocytes Cardiac Tissue Distribution Luciferase Transgenes Myocardial infarction Promoter Regions Genetic 030304 developmental biology 0303 health sciences Myocardium Gene Transfer Techniques Heart Promoter Genetic Therapy Dependovirus medicine.disease 020601 biomedical engineering Mice Inbred C57BL HEK293 Cells Liver |
| Zdroj: | Journal of Tissue Engineering and Regenerative Medicine. 14:123-134 |
| ISSN: | 1932-7005 1932-6254 |
| DOI: | 10.1002/term.2974 |
| Popis: | Adeno-associated viruses (AAV) have become one of the most promising tools for gene transfer in clinics. Among all the serotypes, AAV9 has been described as the most efficient for cardiac transduction. In order to achieve optimal therapeutic delivery in heart disease, we have explored AAV9 transduction efficiency in an infarcted heart using different routes of administration and promoters, including a cardiac-specific one. AAV9 vectors carrying luciferase or green fluorescence protein under the control of the ubiquitous elongation-factor-1-alpha or the cardiac-specific troponin-T (TnT) promoters were administered by intramyocardial or intravenous injection, either in healthy or myocardial-infarcted mice. The transduction efficacy and specificity, the time-course expression, and the safety of each vector were tested. High transgene expression levels were found in the heart, but not in the liver, of mice receiving AAV-TnT, which was significantly higher after intramyocardial injection regardless of ischemia-induction. On the contrary, high hepatic transgene expression levels were detected with the elongation-factor-1-alpha-promoter, independently of the administration route and heart damage. Moreover, tissue-specific green fluorescence protein expression was found in cardiomyocytes with the TnT vector, whereas minimal cardiac expression was detected with the ubiquitous one. Interestingly, we found that myocardial infarction greatly increased the transcriptional activity of AAV genomes. Our findings show that the use of cardiac promoters allows for specific and stable cardiac gene expression, which is optimal and robust when intramyocardially injected. Furthermore, our data indicate that the pathological status of the tissue can alter the transcriptional activity of AAV genomes, an aspect that should be carefully evaluated for clinical applications. |
| Databáze: | OpenAIRE |
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