Key result
rAAV-MHC vectors achieved long-term (16 weeks), cardiac-specific gene expression in vivo without inducing apoptosis in cardiomyocytes compared to adenoviral vectors.
rAAV vectors utilizing the alpha-MHC promoter achieve long-term, cardiomyocyte-specific gene expression in vivo, demonstrating potential for cardiac gene therapy.
May advance preclinical cardiac gene therapy vectors; leaves open translation to human efficacy and safety trials.
Recombinant adeno-associated viral (rAAV) vectors hold promise for delivering genes for heart diseases, but cardiac-specific expression by the use of rAAV has not been demonstrated. To achieve this goal rAAV vectors were generated expressing marker or potentially therapeutic genes under the control of the cardiac muscle-specific alpha myosin heavy chain (MHC) gene promoter. The rAAV-MHC vectors expressed in primary cardiomyocytes with similar kinetics to rAAV-CMV; however, expression by the rAAV-MHC vectors was restricted to cardiomyocytes. rAAV vectors have low cytotoxicity, and it is demonstrated here that rAAV fails to induce apoptosis in cardiomyocytes compared with a recombinant adenoviral vector. rAAV-MHC or rAAV-CMV vectors were administered to mice to determine the specificity of expression in vivo. The rAAV-MHC vectors expressed specifically in cardiomyocytes, whereas the control rAAV-CMV vector expressed in heart, skeletal muscle, and brain. rAAV-MHC transduction resulted in long term (16 weeks) expression of human growth hormone following intracardiac, yet not intramuscular, injection. Finally, we defined the minimal MHC enhancer/promoter sequences required for specific and robust in vivo expression in the context of a rAAV vector. For the first time we describe a panel of rAAV vectors capable of long term cardiac specific expression of intracellular and secreted proteins.
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Aikawa et al. (2002) studied Heart diseases. rAAV-MHC vectors vs. rAAV-CMV vectors and recombinant adenoviral vector was evaluated on Cardiac-specific gene expression and cytotoxicity. rAAV-MHC vectors achieved long-term (16 weeks), cardiac-specific gene expression in vivo without inducing apoptosis in cardiomyocytes compared to adenoviral vectors.
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