Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice

Rita Sarkar, Melinda Mucci, Sankar Addya, Renee Tetreault, Dwight A. Bellinger, Timothy C. Nichols, Haig H. Kazazian

Research output: Contribution to journalArticle

Abstract

We reported total correction of blood coagulation plasma factor VIII (FVIII) activity, using adeno-associated virus serotype 8 (AAV8) vectors for liver-specific gene transfer in hemophilia A mice. We now show, irrespective of immunosuppression or route of administration, total long-term correction of hemophilia A mice with pseudotyped AAV8 and AAV9 vectors. We delivered two FVIII vectors, one expressing canine heavy chain and the other expressing canine light chain. Interestingly, when these vectors were given by hepatic portal vein to hemophilia A dogs, only modest FVIII levels were seen despite the species-specific transgene. No dogs treated developed FVIII inhibitors. However, of three dogs treated with AAV8 vector, the single male, given 1.25 × 1013 genome copies per vector per kilogram (GC/vector/kg), maintained a level of >4.5% for more than 2 years. In contrast, the two female dogs expressed only 2% FVIII activity despite receiving higher doses of 1.52 × 1013 and 3 × 1013 GC/vector/kg, respectively. On the other hand, a male dog treated with AAV9 vector at a low dose (6 × 1012 GC/vector/kg) maintained FVIII levels of 2-2.5% of normal without bleeding for 200 days (observation ongoing). Although hemophilia A mice were not predictive of vector effi in dogs, the two treated male dogs became symptom-free for long periods. Even so, translation of these robust vectors either in appropriate large animals or human beings remains challenging.

Original languageEnglish (US)
Pages (from-to)427-439
Number of pages13
JournalHuman gene therapy
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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