Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy.

Abstract

In a clinical study of recombinant adeno-associated virus-2 expressing human factor IX (AAV2-FIX), we detected 2 impediments to long-term gene transfer. First, preexisting anti-AAV neutralizing antibodies (NABs) prevent vector from reaching the target tissue, and second, CD8(+) T-cell responses to hepatocyte-cell surface displayed AAV-capsid-terminated FIX expression after several weeks. Because the vector is incapable of synthesizing viral proteins, a short course of immunosuppression, until AAV capsid is cleared from the transduced cells, may mitigate the host T-cell response, allowing long-term expression of FIX. To evaluate coad-ministration of immunosuppression, we studied AAV8 vector infusion in rhesus macaques, natural hosts for AAV8. We administered AAV8-FIX in 16 macaques via the hepatic artery and assessed the effects of (1) preexisting anti-AAV8 NABs, (2) a standard T-cell immunosuppressive regimen, and (3) efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NABs abrogate transduction, whereas animals with undetectable NABs are safely and effectively transduced by AAV8-FIX. Coadministration of mycophenolate mofetil and tacrolimus with vector does not induce toxicity and does not impair AAV transduction or FIX synthesis. These findings enable a clinical study to assess the effects of immunomodulation on long-term FIX expression in patients with hemophilia B.

• Authors: Haiyan Jiang, Linda B Couto, Susannah Patarroyo-White, Tongyao Liu, Dea Nagy, Joseph A Vargas, Shangzhen Zhou, Ciaran D Scallan, Jurg Sommer, Sharmila Vijay, Federico Mingozzi, Katherine A High, Glenn F Pierce
• Journal: Blood (Blood) Vol. 108 Issue 10 Pg. 3321-8 (Nov 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16868252 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Factor IX
• Mycophenolic Acid
• Tacrolimus

Topics

• Animals
• Antibodies (pharmacology)
• Dependovirus (genetics, immunology)
• Drug Therapy, Combination
• Factor IX (administration & dosage, immunology)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors (immunology, pharmacokinetics)
• Hemophilia B (therapy)
• Humans
• Immunosuppression Therapy (methods, standards)
• Liver (metabolism)
• Macaca mulatta
• Male
• Mice
• Mycophenolic Acid (administration & dosage, analogs & derivatives)
• Organ Specificity
• Tacrolimus (administration & dosage)