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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3079-3086.
Prepublished online as a Blood First Edition Paper on January 6, 2005; DOI 10.1182/blood-2004-10-3867.
 Previous Article | Next Article 
Submitted October 7, 2004
Accepted December 15, 2004
Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8 mediated, liver-directed gene therapy
Lili Wang, Roberto Calcedo, Timothy C Nichols, Dwight A Bellinger, Aaron Dillow, Inder M Verma, and James M Wilson*
Gene Therapy Program, Department of Medicine, Division of Medical Genetics, University of Pennsylvania, Philadelphia, PA, USA
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA
* Corresponding author; email: wilsonjm{at}mail.med.upenn.edu.
AAV8, a new member of the AAV family isolated from non-human primate, is an attractive candidate for hepatic gene transfer applications because of ten to hundred fold improved transduction efficiency in mouse liver models. Additionally, AAV8 has lesser frequency of pre-existing immunity in humans. These properties could solve some of the problems associated with AAV2 vectors. The benefits of AAV8 demonstrated in mouse models however have not been confirmed in larger animals. In this study, we evaluate the efficacy and safety of AAV2/8 vector in both naive and AAV2-pretreated hemophilia B dogs. Two naive hemophilia B dogs that received a single intraportal administration of AAV2/8 vector have achieved sustained expression of 10% and 26% of normal levels of cFIX for over a year. In an AAV2-pretreated hemophilia B dog, cFIX expression increased from <1% to 16% of normal levels when treated with an AAV2/8 vector and high level of expression has lasted for over two years. No significant liver toxicity or cFIX-specific antibodies have been detected in these animals. Studies here have demonstrated the safety and improved efficacy of AAV2/8 vector in large animal models for liver-directed gene therapy.
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