Effects of Transient Immunosuppression on Adenoassociated, Virus-mediated, Liver-directed Gene Transfer in Rhesus Macaques and Implications for Human Gene Therapy

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2006 Jul 27

PMID 16868252

Citations 195

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

Affiliations

Soon will be listed here.

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.

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