Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver
Open Access
- 1 October 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (7), 2334-2341
- https://doi.org/10.1182/blood-2007-03-080093
Abstract
Adeno-associated virus (AAV)–mediated gene transfer of factor IX (F.IX) to the liver results in long-term expression of transgene in experimental animals, but only short-term expression in humans. Loss of F.IX expression is likely due to a cytotoxic immune response to the AAV capsid, which results in clearance of transduced hepatocytes. We used a nonhuman primate model to assess the safety of AAV gene transfer coupled with an anti–T-cell regimen designed to block this immune response. Administration of a 3-drug regimen consisting of mycophenolate mofetil (MMF), sirolimus, and the anti–IL-2 receptor antibody daclizumab consistently resulted in formation of inhibitory antibodies to human F.IX following hepatic artery administration of an AAV-hF.IX vector, whereas a 2-drug regimen consisting only of MMF and sirolimus did not. Administration of daclizumab was accompanied by a dramatic drop in the population of CD4+CD25+FoxP3+ regulatory T cells (Tregs). We conclude that choice of immunosuppression (IS) regimen can modulate immune responses to the transgene product upon hepatic gene transfer in subjects not fully tolerant; and that induction of transgene tolerance may depend on a population of antigen-specific Tregs.Keywords
This publication has 40 references indexed in Scilit:
- Pre-existing AAV Capsid-specific CD8+ T Cells are Unable to Eliminate AAV-transduced HepatocytesMolecular Therapy, 2007
- Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuriaExperimental & Molecular Medicine, 2006
- Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapyBlood, 2006
- Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conferenceHaemophilia, 2006
- Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primatesBlood, 2006
- Role of cellular FKBP52 protein in intracellular trafficking of recombinant adeno-associated virus 2 vectorsVirology, 2006
- Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001–2003Haemophilia, 2005
- Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cellsBlood, 2005
- Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vectorBlood, 2003
- Risk and Prevention of Anti-factor IX Formation in AAV-Mediated Gene Transfer in the Context of a Large Deletion of F9Molecular Therapy, 2001