Abstract:
:Newly isolated serotypes of AAV readily cross the endothelial barrier to provide efficient transgene delivery throughout the body. However, tissue-specific expression is preferred in most experimental studies and gene therapy protocols. Previous efforts to restrict gene expression to the myocardium often relied on direct injection into heart muscle or intracoronary perfusion. Here, we report an AAV vector system employing the cardiac troponin T (cTnT) promoter. Using luciferase and enhanced green fluorescence protein (eGFP), the efficiency and specificity of cardiac reporter gene expression using AAV serotype capsids: AAV-1, 2, 6, 8 or 9 were tested after systemic administration to 1-week-old mice. Luciferase assays showed that the cTnT promoter worked in combination with each of the AAV serotype capsids to provide cardiomyocyte-specific gene expression, but AAV-9 followed closely by AAV-8 was the most efficient. AAV9-mediated gene expression from the cTnT promoter was 640-fold greater in the heart compared with the next highest tissue (liver). eGFP fluorescence indicated a transduction efficiency of 96% using AAV-9 at a dose of only 3.15 × 10(10) viral particles per mouse. Moreover, the intensity of cardiomyocyte eGFP fluorescence measured on a cell-by-cell basis revealed that AAV-mediated gene expression in the heart can be modeled as a Poisson distribution, requiring an average of nearly two vector genomes per cell to attain an 85% transduction efficiency.
journal_name
Gene Therjournal_title
Gene therapyauthors
Prasad KM,Xu Y,Yang Z,Acton ST,French BAdoi
10.1038/gt.2010.105subject
Has Abstractpub_date
2011-01-01 00:00:00pages
43-52issue
1eissn
0969-7128issn
1476-5462pii
gt2010105journal_volume
18pub_type
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