Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue.
BACKGROUND
The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an ideal vector supporting safe and long-term myocardial transgene expression.


RESULTS
Here, we show that the use of a recombinant adeno-associated viral (rAAV6) vector containing a novel cardiac-selective enhancer/promoter element can direct stable cardiac expression of a therapeutic transgene, the calcium (Ca2+)-sensing S100A1, in a rat model of heart failure. The chronic heart failure-rescuing properties of myocardial S100A1 expression, the result of improved sarcoplasmic reticulum Ca2+ handling, included improved contractile function and left ventricular remodeling. Adding to the clinical relevance, long-term S100A1 therapy had unique and additive beneficial effects over beta-adrenergic receptor blockade, a current pharmacological heart failure treatment.


CONCLUSIONS
These findings demonstrate that stable increased expression of S100A1 in the failing heart can be used for long-term reversal of LV dysfunction and remodeling. Thus, long-term, cardiac-targeted rAAV6-S100A1 gene therapy may be of potential clinical utility in human heart failure.
Pleger
Sven T
ST
Center for Translational Medicine and George Zallie and Family Laboratory of Cardiovascular Gene Therapy, Thomas Jefferson University, 1025 Walnut St, Room 317, Philadelphia, PA 19107, USA.
Most
Patrick
P
Boucher
Matthieu
M
Soltys
Stephen
S
Chuprun
J Kurt
JK
Pleger
Wiebke
W
Gao
Erhe
E
Dasgupta
Abhijit
A
Rengo
Giuseppe
G
Remppis
Andrew
A
Katus
Hugo A
HA
Eckhart
Andrea D
AD
Rabinowitz
Joseph E
JE
Koch
Walter J
WJ
D000199:Actins / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000517:prevention & control; D000229:Dependovirus / Q000235:genetics; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000235:genetics; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D006334:Heart Function Tests; D006801:Humans; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D009418:S100 Proteins / Q000235:genetics / Q000502:physiology*
D000199:Actins; D011993:Recombinant Fusion Proteins; D009418:S100 Proteins; C110294:S100A1 protein; D049452:Green Fluorescent Proteins