" Gene Therapy Targets for Heart Failure "
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Abstract: We have spent the last decade investigating both novel molecular targets for correcting ventricular dysfunction in heart failure and also novel delivery methods for genetic material for gene therapy protocols.  Using genetically engineered mouse models, two important targets have emerged that appear to thwart the development of various cardiomyopathies.  These are first a peptide inhibitor of the b-adrenergic receptor kinase (bARK1 or GRK2) known as the bARKct and more recently, we have found the cardiac calcium binding and sensing protein S100A1 is a target for heart failure.  S100A1 is significantly down-regulated in heart failure and we have recently shown that normalization of levels of this protein in the both the acute and failing heart can reverse and/or prevent ventricular dysfunction through actions in the sarcoplasmic reticulum (SR) at both the Ca-ATPase, SERCA, and the ryanodine receptor (RyR).  Using adenoviral vectors, we have developed intracoronary gene delivery techniques to both small and large animals and have shown that the bARKct and S100A1 are powerful molecular therapeutics.  In this lecture our current status in these areas will be discussed including mechanistic studies and the use of the bARKct and S100A1 together in the heart.