Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B
- Valder R. Arruda1,
- Hansell H. Stedman1,
- Virginia Haurigot2,
- George Buchlis1,
- Stefano Baila3,
- Patricia Favaro3,
- Yifeng Chen2,
- Helen G. Franck4,
- Shangzhen Zhou3,
- J. Fraser Wright3,
- Linda B. Couto3,
- Haiyan Jiang5,
- Glenn F. Pierce5,
- Dwight A. Bellinger4,
- Federico Mingozzi3,
- Timothy C. Nichols4, and
- Katherine A. High3,*
- 1 University of Pennsylvania School of Medicine, Philadelphia, PA, United States;
- 2 Howard Hughes Medical Institute, Philadelphia, PA, United States;
- 3 The Children's Hospital of Philadelphia, Philadelphia, PA, United States;
- 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;
- 5 Biogen Idec, Inc., Waltham, MA, United States
- * Corresponding author; email: high{at}email.chop.edu
Abstract
Muscle represents an important tissue target for adeno-associated viral (AAV) vector-mediated gene transfer of the factor IX (FIX) gene in hemophilia B (HB) subjects with advanced liver disease. Previous studies of direct intramuscular administration of an AAV-FIX vector in humans showed limited efficacy. Here we adapted an intravascular delivery system of AAV vectors encoding the FIX transgene to skeletal muscle of HB dogs. The procedure, performed under transient immunosuppression (IS), resulted in widespread transduction of muscle and sustained, dose-dependent therapeutic levels of canine FIX transgene up to 10-fold higher than those obtained by intramuscular delivery. Correction of bleeding time correlated clinically with a dramatic reduction of spontaneous bleeding episodes. None of the dogs (n=14) receiving the AAV vector under transient IS developed inhibitory antibodies to cFIX; transient inhibitor was detected following vector delivery with no IS. The use of AAV serotypes with high tropism for muscle and low susceptibility to anti-AAV-2 antibodies allowed for efficient vector administration in naïve dogs and in the presence of low-titer but not high-titer anti-AAV2 antibodies. Collectively, these results demonstrate the feasibility of this approach for the treatment of HB and highlight the importance of IS to prevent immune responses to the FIX transgene product.
- Submitted December 28, 2009.
- Accepted March 9, 2010.
- Copyright © 2005 American Society of Hematology
