Blood online
Home About Blood Authors Subscriptions Permission Advertising Public Access contact us
 

 
Advanced
Current Issue
First Edition
Archives
Submit to Blood
Search
American Society of Hematology
Meeting Abstracts
Email Alerts
 Blood, 15 November 2006, Vol. 108, No. 10, pp. 3321-3328.
Prepublished online as a Blood First Edition Paper on July 25, 2006; DOI 10.1182/blood-2006-04-017913.

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
blood-2006-04-017913v1
108/10/3321    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jiang, H.
Right arrow Articles by Pierce, G. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, H.
Right arrow Articles by Pierce, G. F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

arrow to previous article Previous Article  |  Next Article next article arrow

Submitted April 18, 2006
Accepted July 7, 2006

Effects of transient immunosuppression on adeno associated virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy

Haiyan Jiang*, Linda B. Couto, Susannah Patarroyo-White, Tongyao Liu, Dea Nagy, Joseph A. Vargas, Shangzhen Zhou, Ciaran D. Scallan, Jurg Sommer, Sharmila Vijay, Darren Warren, Federico Mingozzi, Katherine A. High, and Glenn F. Pierce

Bayer HealthCare, LLC
Benitec, Inc.
Avigen, Inc.
BayerHealth Care, LLC
Howard Hughes Medical Institute,The Children's Hospital of Philadelphia
Bayer HealthCare LLC
Charles River Laboratories
Howard Hughes Medical Institute, The Children's Hospital of Philadelphia
Bayer Healthcare, LLC

* Corresponding author; email: haiyan.jiang.b{at}bayer.com.

In a clinical study of recombinant adeno-associated virus-2 expressing human Factor IX (AAV2-FIX), we detected two impediments to long-term gene transfer. First, pre-existing anti-AAV neutralizing antibodies (NAB) prevent vector from reaching the target tissue; second, CD8+ T-cell responses to hepatocyte cell surface-displayed AAV capsid terminated FIX expression after several weeks. Since the vector is incapable of synthesizing viral proteins, a short course of immunosuppression, until AAV capsid is cleared from the transduced cells, may mitigate the host T-cell response, allowing long-term expression of FIX. To evaluate co-administration of immunosuppression, we studied AAV8 vector infusion in rhesus macaques, natural hosts for AAV8. We administered AAV8-FIX in 16 macaques via the hepatic artery and assessed the effects of [1] pre-existing anti-AAV8 neutralizing antibodies (NAB), [2] a standard immunosuppressive (IS) regimen, and [3] efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NAB abrogate transduction, whereas animals with undetectable NAB are safely and effectively transduced by AAV8-FIX. Co-administration of mycophenolate mofetil and tacrolimus with vector does not induce toxicity and does not impair AAV transduction or FIX synthesis. These findings enable a clinical study to assess the effects of immunomodulation on long-term FIX expression in hemophilia B patients.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




click for free articles
home about blood authors subscriptions permissions advertising public access contact us
  Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020