Journal
BLOOD
Volume 103, Issue 1, Pages 85-92Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2003-05-1446
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Funding
- NHLBI NIH HHS [P01 HL064190, P01 HL64190, R24 HL063098, R24 HL63098] Funding Source: Medline
- NIDDK NIH HHS [K01 DK060580, K01 DK60580-01] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R24HL063098, P01HL064190] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K01DK060580] Funding Source: NIH RePORTER
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Adeno-associated viral (AAV) vectors (serotype 2) efficiently transduce skeletal muscle, and have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimental animals and humans. Recent reports suggest that AAV vectors based on serotypes 1, 5, and 7 transduce murine skeletal muscle much more efficiently than AAV-2, with reported increases in expression ranging from 2-fold to 1000-fold. We sought to determine whether this increased efficacy could be observed in species other than mice. In Immunodeficient mice we saw 10- to 20-fold higher levels of human factor IX (hF.IX) expression at a range of doses, and in hemophilic dogs we observed approximately 50-fold higher levels of expression. The increase in transgene expression was due partly to higher gene copy number and a larger number of cells transduced at each injection site. In all immunocompatent animals injected with AAV-1, inhibitory antibodies to F.IX developed, but in immunocompetent mice treated with high doses of vector, inhibitory antibodies eventually disappeared. These studies emphasize that the increased efficacy of AAV-1 vectors carries a risk of inhibitor formation, and that further studies will be required to define doses and treatment regimens that result in tolerance rather than immunity to F.IX.
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