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

 
Advanced
Current Issue
First Edition
Future Articles
Archives
Submit to Blood
Search
American Society of Hematology
Meeting Abstracts
Email Alerts
Blood, 1 October 2007, Vol. 110, No. 7, pp. 2334-2341.
Prepublished online as a Blood First Edition Paper on July 3, 2007; DOI 10.1182/blood-2007-03-080093.


This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
blood-2007-03-080093v1
110/7/2334    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 HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mingozzi, F.
Right arrow Articles by High, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mingozzi, F.
Right arrow Articles by High, K. A.
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 March 14, 2007
Accepted June 21, 2007

Modulation of tolerance to the transgene product in a non-human primate model of AAV-mediated gene transfer to liver

Federico Mingozzi, Nicole C. Hasbrouck, Etiena Basner-Tschkarajan, Shyrie A. Edmonson, Daniel J. Hui, Denise E. Sabatino, Shangzhen Zhou, J. Fraser Wright, Haiyan Jiang, Glenn F Pierce, Valder R. Arruda, and Katherine A. High*

Division of Hematology, Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Howard Hughes Medical Institute, Philadelphia, PA, United States
University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
Clinical Development, Avigen, Inc., Alameda, CA, United States

* Corresponding author; email: high{at}email.chop.edu.

Adeno-associated virus (AAV)-mediated gene transfer of Factor IX (F.IX) to the liver results in long-term expression of transgene in experimental animals, but only short-term expression in humans. Loss of F.IX expression is likely due to a cytotoxic immune response to the AAV capsid, which results in clearance of transduced hepatocytes. We used a non-human primate model to assess the safety of AAV gene transfer coupled with an anti-T cell regimen designed to block this immune response. Administration of a 3-drug regimen consisting of mycophenolate mofetil (MMF), sirolimus, and the anti-IL-2 receptor antibody daclizumab consistently resulted in formation of inhibitory antibodies to human F.IX following hepatic artery administration of an AAV-hF.IX vector, whereas a 2-drug regimen consisting only of MMF and sirolimus did not. Administration of daclizumab was accompanied by a dramatic drop in the population of CD4+, CD25+, FoxP3+ regulatory T cells (Tregs). We conclude that choice of IS regimen can modulate immune responses to the transgene product upon hepatic gene transfer in subjects not fully tolerant; and that induction of transgene tolerance may depend upon a population of antigen-specific Tregs.


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?


This article has been cited by other articles:


Home page
BloodHome page
F. Mingozzi, J. J. Meulenberg, D. J. Hui, E. Basner-Tschakarjan, N. C. Hasbrouck, S. A. Edmonson, N. A. Hutnick, M. R. Betts, J. J. Kastelein, E. S. Stroes, et al.
AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells
Blood, September 3, 2009; 114(10): 2077 - 2086.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
B. Peng, P. Ye, B. R. Blazar, G. J. Freeman, D. J. Rawlings, H. D. Ochs, and C. H. Miao
Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice
Blood, September 1, 2008; 112(5): 1662 - 1672.
[Abstract] [Full Text] [PDF]


Home page
J. Virol.Home page
G. D. King, A. K. M. G. Muhammad, W. Xiong, K. M. Kroeger, M. Puntel, D. Larocque, D. Palmer, P. Ng, P. R. Lowenstein, and M. G. Castro
High-Capacity Adenovirus Vector-Mediated Anti-Glioma Gene Therapy in the Presence of Systemic Antiadenovirus Immunity
J. Virol., May 1, 2008; 82(9): 4680 - 4684.
[Abstract] [Full Text] [PDF]



 click for free articles
home about blood authors subscriptions permissions advertising public access contact us
  Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020