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Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction

Gene Therapy volume 23, pages 151–157 (2016)Cite this article

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Abstract

The S100A1 gene is a promising target enhancing contractility and survival post myocardial infarction (MI). Achieving sufficient gene delivery within safety limits is a major translational problem. This proof of concept study evaluates viral mediated S100A1 overexpression featuring a novel liquid jet delivery (LJ) method. Twenty-four rats after successful MI were divided into three groups (n=8 ea.): saline control (SA); ssAAV9.S100A1 (SS) delivery; and scAAV9.S100A1 (SC) delivery (both 1.2 × 1011 viral particles). For each post MI rat, the LJ device fired three separate 100 μl injections into the myocardium. Following 10 weeks, all rats were evaluated with echocardiography, quantitative PCR (qPCR) and overall S100A1 and CD38 immune protein. At 10 weeks all groups demonstrated a functional decline from baseline, but the S100A1 therapy groups displayed preserved left ventricular function with significantly higher ejection fraction %; SS group (60±3) and SC group (57±4) versus saline (46±3), P<0.05. Heart qPCR testing showed robust S100A1 in the SS (10 147±3993) and SC (35 155±5808) copies per 100 ng DNA, while off-target liver detection was lower in both SS (40±40), SC (34 841±3164), respectively. Cardiac S100A1 protein expression was (4.3±0.2) and (6.1±0.3) fold higher than controls in the SS and SC groups, respectively, P<0.05.

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Acknowledgements

This study was graciously supported by the Heineman Foundation as well as NIH grant 2-R01 HL083078-08. We acknowledge the Gene Therapy Resource Program (GTRP) of the National Heart, Lung and Blood Institute for their gracious support in providing all AAV vectors necessary for this study, in particular Dr Julie Johnston for custom analysis in the design phase. We also thank the Vivarium staff at Carolinas Medical Center for their outstanding effort with supporting the procedures and post-operative care and Dr Sriparna Ghosh who performed all of the Confocal microscopy analysis. This study received support from the Heineman Foundation, NIH grant 2-R01 HL083078-08, and the Gene Therapy Resource Program (GTRP) of the National Heart, Lung and Blood Institute.

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Authors and Affiliations

  1. Department of Thoracic and Cardiac Surgery, Sanger Heart and Vascular Institute, Carolinas HealthCare System, Charlotte, NC, USA

    A S Fargnoli, M G Katz, R D Williams, A P Kendle & C R Bridges

  2. Department of Therapeutic Research and Development, Molecular Biology Core, Cannon Research Center, Carolinas HealthCare System, Charlotte, NC, USA

    N Steuerwald

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  1. A S Fargnoli
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  2. M G Katz
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Correspondence to A S Fargnoli.

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Fargnoli, A., Katz, M., Williams, R. et al. Liquid jet delivery method featuring S100A1 gene therapy in the rodent model following acute myocardial infarction. Gene Ther 23, 151–157 (2016). https://doi.org/10.1038/gt.2015.100

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