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Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

Gene Therapy volume 23, pages 313–319 (2016)Cite this article

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Abstract

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

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Acknowledgements

Sharon L Cross provided medical writing support and Julia Andres provided graphics support on behalf of Celladon Corporation. Dr Thomas Weber provided critical editing of the manuscript. RJH is supported by NIH R01 HL 117505, HL 119046, a P50 HL112324 and a Transatlantic Fondation Leducq grant.

Author contributions

BG, JMP, RP, JG, RJH and KMZ were involved in study conception and design. BG, JB, GMF, PP, AAV and RJH were involved in data collection. JMP provided statistical analyses. BG wrote the first draft of the manuscript. All authors were involved in manuscript revision and approved the final version.

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Authors and Affiliations

  1. Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, CA, USA

    B Greenberg

  2. Stony Brook University, Stony Brook, NY, USA

    J Butler

  3. Duke University School of Medicine, Durham, NC, USA

    G M Felker

  4. Wroclaw Medical University and Military Hospital, Wroclaw, Poland

    P Ponikowski

  5. University of Groningen, Groningen, The Netherlands

    A A Voors

  6. Celladon Corporation, San Diego, CA, USA

    J M Pogoda, R Provost & J Guerrero

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

    R J Hajjar

  8. Biovest Consulting, LLC, Santa Barbara, CA, USA

    K M Zsebo

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  1. B Greenberg
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  2. J Butler
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  10. K M Zsebo
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Corresponding author

Correspondence to B Greenberg.

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Competing interests

This study was funded by Celladon Corporation (San Diego, CA, USA). Drs Greenberg, Butler, Felker, Ponikowski, Voors and Hajjar have received compensation for consultancies or board memberships from Celladon Corporation, the sponsor of this study. Drs Pogoda, Provost, Guerrero and Zsebo are former employees of Celladon.

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Greenberg, B., Butler, J., Felker, G. et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure. Gene Ther 23, 313–319 (2016). https://doi.org/10.1038/gt.2015.109

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  • DOI: https://doi.org/10.1038/gt.2015.109

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