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Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart

Gene Therapy volume 23, pages 296–305 (2016)Cite this article

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Abstract

Gene therapy is a promising new treatment option for cardiac diseases. For finding the most suitable and safe vector for cardiac gene transfer, we delivered adenovirus (AdV), adeno-associated virus (AAV) and lentivirus (LeV) vectors into the mouse heart with sophisticated closed-chest echocardiography-guided intramyocardial injection method for comparing them with regards to transduction efficiency, myocardial damage, effects on the left ventricular function and electrocardiography (ECG). AdV had the highest transduction efficiency in cardiomyocytes followed by AAV2 and AAV9, and the lowest efficiency was seen with LeV. The local myocardial inflammation and fibrosis in the left ventricle (LV) was proportional to transduction efficiency. AdV caused LV dilatation and systolic dysfunction. Neither of the locally injected AAV serotypes impaired the LV systolic function, but AAV9 caused diastolic dysfunction to some extent. LeV did not affect the cardiac function. We also studied systemic delivery of AAV9, which led to transduction of cardiomyocytes throughout the myocardium. However, also diffuse fibrosis was present leading to significantly impaired LV systolic and diastolic function and pathological ECG changes. Compared with widely used AdV vector, AAV2, AAV9 and LeV were less effective in transducing cardiomyocytes but also less harmful. Local administration of AAV9 was safer and more efficient compared with systemic administration.

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Acknowledgements

This work was supported by grants from Finnish Academy, ERC, Finnish Foundation for Cardiovascular Diseases, Sigrid Juselius Foundation and Kuopio University Hospital, Summit (Grant Agreement number 115006, IMI). We thank Sari Järveläinen, Tiina Koponen, Tuula Salonen, Anne Martikainen and Seija Sahrio for technical assistance and the staff at The National Laboratory Animal Center of the University of Eastern Finland (Kuopio campus) for maintenance of the animals. pDG helper plasmid was a kind gift from Dr Jürgen A Kleinschmidt, (German Cancer Research Center, Heidelberg, Germany).

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Author notes

  1. L Lottonen-Raikaslehto and V Parviainen: These authors contributed equal to this work.

Authors and Affiliations

  1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    M Merentie, L Lottonen-Raikaslehto, V Parviainen, J Huusko, S Pikkarainen, M Mendel, N Laham-Karam, R Rissanen & S Ylä-Herttuala

  2. Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland

    M Mendel

  3. Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

    V Kärjä

  4. Heart Center, Kuopio University Hospital, Kuopio, Finland

    M Hedman

  5. Diagnostic Imaging Center, Kuopio University Hospital, Kuopio, Finland

    M Hedman

  6. Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

    S Ylä-Herttuala

  7. Science Service Center, Kuopio University Hospital, Kuopio, Finland

    S Ylä-Herttuala

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  1. M Merentie
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Correspondence to S Ylä-Herttuala.

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Merentie, M., Lottonen-Raikaslehto, L., Parviainen, V. et al. Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart. Gene Ther 23, 296–305 (2016). https://doi.org/10.1038/gt.2015.114

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  • DOI: https://doi.org/10.1038/gt.2015.114

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