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 December 2003, Vol. 102, No. 12, pp. 3919-3926.
Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-01-0222.

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2003-01-0222v1
102/12/3919    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 Scallan, C. D.
Right arrow Articles by Couto, L. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scallan, C. D.
Right arrow Articles by Couto, L. B.
Related Collections
Right arrow Hemostasis, Thrombosis, and Vascular Biology
Right arrow Gene Expression
Right arrow Gene Therapy
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  |  Table of Contents  |  Next Article next article arrow

GENE THERAPY

Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII

Ciaran D. Scallan, Tongyao Liu, Amy E. Parker, Susannah L. Patarroyo-White, Haifeng Chen, Haiyan Jiang, Joseph Vargas, Dea Nagy, Sharon K. Powell, J. Fraser Wright, Rita Sarkar, Haig H. Kazazian, Alan McClelland, and Linda B. Couto

From Avigen Inc., Alameda, CA; and the Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, PA.

Using separate adeno-associated viral 2 (AAV2) vectors to deliver the heavy and light chains of factor VIII (FVIII) we have overcome the packaging limitations of AAV, achieving phenotypic correction of hemophilia A in mice. AAV vectors were constructed that use a liver-specific promoter and the cDNA sequences of either the human or canine heavy and light chains of FVIII. After intraportal vein injection of these vectors in hemophilia-A mice, therapeutic to superphysiologic levels of active FVIII were achieved in plasma in a dose-dependent manner. Phenotypic correction of the bleeding diathesis was demonstrated by survival of all treated mice after tail clipping. Biochemical analysis demonstrated lower levels of heavy-chain (25- to 100-fold) compared with light-chain protein in the plasma of treated animals. Differences in gene transfer and transcription did not account for the differences in protein expression. We hypothesize that improvements in FVIII activity could be achieved by improvements in FVIII heavy-chain expression. This work demonstrates that cotransduction of liver with AAV vectors expressing the heavy and light chains of FVIII corrects hemophilia A in vivo, providing an alternative approach to the use of a single vector. This strategy may potentially be useful for other large therapeutic proteins that contain functionally distinct domains.


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
 ASH Education BookHome page
K. A. High
Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia
Hematology, January 1, 2007; 2007(1): 466 - 472.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Xu, T. C. Nichols, R. Sarkar, S. McCorquodale, D. A. Bellinger, and K. P. Ponder
Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy
PNAS, April 26, 2005; 102(17): 6080 - 6085.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
E. Dobrzynski, F. Mingozzi, Y.-L. Liu, E. Bendo, O. Cao, L. Wang, and R. W. Herzog
Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer
Blood, August 15, 2004; 104(4): 969 - 977.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. Sarkar, R. Tetreault, G. Gao, L. Wang, P. Bell, R. Chandler, J. M. Wilson, and H. H. Kazazian Jr
Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype
Blood, February 15, 2004; 103(4): 1253 - 1260.
[Abstract] [Full Text] [PDF]


click for free articles
home about blood authors subscriptions permissions advertising public access contact us
  Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020