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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-06-2181.
Submitted July 1, 2003
Accepted September 3, 2003
Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs
Jun Zhang, Lingfei Xu, Mark E Haskins, and Katherine Parker Ponder*
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
* Corresponding author; email: kponder{at}im.wustl.edu.
The effect of neonatal gene transfer upon antibody formation was determined using a retroviral vector (RV) expressing human FIX (hFIX). Normal mice from different strains that were injected IV with RV as newborns achieved therapeutic levels of hFIX without antibody production, and were tolerant as adults to challenge with hFIX. Neonatal hemophilia B mice that received different amounts of RV achieved stable and dose-related expression of hFIX without anti-hFIX antibody formation. After protein challenge, antibody formation was markedly reduced for animals that expressed hFIX at >14 ng/ml (0.3% of normal). However, antibodies developed for animals that received the lowest dose of RV, who expressed hFIX at ~2 ng/ml prior to protein challenge. In dogs, neonatal injection of a high dose of RV resulted in 500 ng/ml of hFIX in plasma without antibody formation. We conclude that neonatal gene transfer with an RV does not induce antibody responses to hFIX in mice or dogs, and mice that achieve >3x10-10 M of hFIX are usually tolerant to protein injection as adults. Low dose gene therapy or frequent protein injections in the neonatal period might induce tolerance to subsequent injection of protein with a low risk of adverse effects.
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