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Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure

Gene Therapy volume 21, pages 379–386 (2014)Cite this article

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Abstract

Adeno-associated virus (AAV)-based vectors are promising vehicles for therapeutic gene delivery, including for the treatment for heart failure. It has been demonstrated for each of the AAV serotypes 1 through 8 that inhibition of the proteasome results in increased transduction efficiencies. For AAV9, however, the effect of proteasome inhibitors on in vivo transduction has until now not been evaluated. Here we demonstrate, in a well-established rodent heart failure model, that concurrent treatment with the proteasome inhibitor bortezomib does not enhance the efficacy of AAV9.SERCA2a to improve cardiac function as examined by echocardiography and pressure volume analysis. Western blot analysis of SERCA2a protein and reverse transcription-PCR of SERCA2a mRNA demonstrated that bortezomib had no effect on either endogenous rat SERCA2a levels nor on expression levels of human SERCA2a delivered by AAV9.SERCA2a. Similarly, the number of AAV9 genomes in heart samples was unaffected by bortezomib treatment. Interestingly, whereas transduction of HeLa cells and neonatal rat cardiomyocytes by AAV9 was stimulated by bortezomib, transduction of adult rat cardiomyocytes was inhibited. These results indicate an organ/cell-type-specific effect of proteasome inhibition on AAV9 transduction. A future detailed analysis of the underlying molecular mechanisms promises to facilitate the development of improved AAV vectors.

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Acknowledgements

This work was supported by NIH R01 HL093183 (RJH), HL088434 (RJH), HL097108 (FGA), P20 HL100396 (RJH), P50 HL112324 (RJH), NHLBI Program of Excellence in Nanotechnology (PEN) Award, contract number HHSN268201000045C (Zahi Fayad, Mount Sinai) and K08 HL111330 (JCK).

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  1. A H Chaanine and M Nonnenmacher: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    A H Chaanine, M Nonnenmacher, E Kohlbrenner, D Jin, J C Kovacic, F G Akar, R J Hajjar & T Weber

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  1. A H Chaanine
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Correspondence to T Weber.

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Competing interests

Dr Hajjar is the scientific cofounder of Celladon, which plans to commercialize AAV1.SERCA2a for the treatment of HF. The remaining authors declare no conflict of interest.

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Chaanine, A., Nonnenmacher, M., Kohlbrenner, E. et al. Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Ther 21, 379–386 (2014). https://doi.org/10.1038/gt.2014.7

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