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A Needleless Liquid Jet Injection Delivery Method for Cardiac Gene Therapy: a Comparative Evaluation Versus Standard Routes of Delivery Reveals Enhanced Therapeutic Retention and Cardiac Specific Gene Expression

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Abstract

This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n = 24 rats), retention of dye was evaluated 10 min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52 ± 4] % and LVIC-OCCL [58 ± 3] % groups p < 0.05 compared with IM [31 ± 8] % and LVIC [35 ± 4] %. In the second (n = 16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6 weeks post-delivery, a similar trend was found with liquid jet [54 ± 5] % and LVIC-OCCL [60 ± 8] % featuring more LV expression as compared with IM [30 ± 9] % and LVIC [23 ± 9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery.

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Acknowledgments

This work was supported by the National Heart, Lung and Blood Institute R01 grant #2R01HL083078-05. Gracious support was received from the Gene Therapy Resource Program in providing all rAAV vectors for the animal studies. In addition, we received support from the Heineman Research Foundation in Charlotte for seed funding. We also acknowledge Tracy Walling MS in the Cannon Research Center for assisting with all the histology work and Dr. Paulo Arratia at the Complex Fluids Laboratory for the device measurements.

Disclosure Statement

No competing financial interests exist.

Funding Source

National Heart, Lung and Blood Institute (2-R01-HL083078-05).

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Authors and Affiliations

  1. Sanger Heart & Vascular Institute, Thoracic and Cardiac Surgery, Cannon Research Center, Carolinas Healthcare System, 1542 Garden Terrace, Charlotte, NC, 28203, USA

    A. S. Fargnoli, M. G. Katz, R. D. Williams & Charles R. Bridges

  2. School of Engineering and Applied Science, Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    A. S. Fargnoli

  3. Perelman School of Medicine, Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA

    K. B. Margulies

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  1. A. S. Fargnoli
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  2. M. G. Katz
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Correspondence to Charles R. Bridges.

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Editor-in-chief Jennifer L. Hall oversaw the review of this article.

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Fargnoli, A.S., Katz, M.G., Williams, R.D. et al. A Needleless Liquid Jet Injection Delivery Method for Cardiac Gene Therapy: a Comparative Evaluation Versus Standard Routes of Delivery Reveals Enhanced Therapeutic Retention and Cardiac Specific Gene Expression. J. of Cardiovasc. Trans. Res. 7, 756–767 (2014). https://doi.org/10.1007/s12265-014-9593-1

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  • DOI: https://doi.org/10.1007/s12265-014-9593-1

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