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Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Gene Therapy volume 19, pages 288–294 (2012)Cite this article

Abstract

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

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Acknowledgements

We thank Matt Hirsch for his critical reading and comments. This work was in part supported from NIH research grants 1R01AI080726 and 5R01DK084033 (to CL and RJS), 5U54AR056953 and 5R01AI072176 (to RJS). This report documents a satellite study of the Joint Outcome Study; the parent study JOS was supported by grants from the Centers for Disease Control and Prevention (U27/CCU812106) and the National Institutes of Health (R00069) and additionally received support from Bayer HealthCare and the Hemophilia and Thrombosis Research Society.

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Author notes

  1. C Li, N Narkbunnam, R J Samulski, A Asokan, G Hu, L J Jacobson, M J Manco-Johnson and P E Monahan: Joint Outcome Study Investigators are listed in the Appendix.

Authors and Affiliations

  1. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    C Li, N Narkbunnam, R J Samulski, A Asokan, G Hu & P E Monahan

  2. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    C Li & P E Monahan

  3. Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    N Narkbunnam

  4. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    R J Samulski

  5. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    A Asokan

  6. Department of Pediatrics, Hemophilia and Thrombosis Center, University of Colorado Denver, Denver, CO, USA

    L J Jacobson & M J Manco-Johnson

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Correspondence to P E Monahan.

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APPENDIX

APPENDIX

The joint outcome study investigators and affiliated institutions

Marilyn J Manco-Johnson, MD, Brenda Riske, MS, MBA, MPA, Ray Kilcoyne, Michael L Manco-Johnson, MD, Sharon Funk, BSc, PT, Linda Jacobson, BS, J David Ingram, MD (all affiliated with the University of Colorado and Health Sciences Center and/or the Children's Hospital, Denver, CO), Thomas C Abshire, MD (Emory University, Atlanta, GA; current address: The Blood Center of Milwaukee), Amy D Shapiro, MD (Indiana Hemophilia and Thrombosis Center, Indianapolis), Michele R Hacker, ScD (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA), Leonard A Valentino, MD (Rush Children's Hospital, Chicago, IL), W Keith Hoots, MD and Deborah Brown, MD (University of Texas, Houston, TX), George R Buchanan, MD (University of Southwestern Medical Center Donna DiMichele, MD (Weill Medical College of Cornell University, New York), Michael Recht, MD, PhD (Phoenix Children's Hospital, Phoenix, AZ), Cindy Leissinger, MD (Tulane University, New Orleans, LA), Shirley Bleak, MSN (Primary Children's Hospital, Salt Lake City, UT), Alan Cohen, MD (University of Pennsylvania, Children's Hospital of Philadelphia, PA), Prasad Mathew, MD (University of New Mexico, Albuquerque, NM), Alison Matsunaga, MD (Oakland Children's Hospital, Oakland, CA), Desiree Medeiros, MD (University of Hawaii, Honolulu), Diane Nugent, MD (Children's Hospital of Orange County, CA), Gregory A Thomas, MD (Oregon Health and Sciences University, Portland, OR), Alexis A Thompson, MD (Children's Memorial Hospital and Northwestern University, Chicago, IL), Kevin McRedmond, MD (Palmetto Health Richland, Columbia, SC), J Michael Soucie, PhD, and Harlan Austin, PhD and Bruce L Evatt, MD (Centers for Disease Control and Prevention, Atlanta, GA).

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Li, C., Narkbunnam, N., Samulski, R. et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther 19, 288–294 (2012). https://doi.org/10.1038/gt.2011.90

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