An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells
Multiple independent adeno-associated virus (AAV) gene therapy clinical trials for hemophilia B, utilizing different AAV serotypes, have reported a vector dose-dependent loss of circulating factor IX (FIX) protein associated with capsid-specific CD8+ T cell (Cap-CD8) elimination of transduced hepato...
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doaj-8cb46ba869564c8980d91cf54bc5ee632020-11-24T20:57:48ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-06-015C14215210.1016/j.omtm.2017.04.004An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T CellsBrett Palaschak0Damien Marsic1Roland W. Herzog2Sergei Zolotukhin3David M. Markusic4Department of Pediatrics, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, University of Florida, Gainesville, FL 32610, USAMultiple independent adeno-associated virus (AAV) gene therapy clinical trials for hemophilia B, utilizing different AAV serotypes, have reported a vector dose-dependent loss of circulating factor IX (FIX) protein associated with capsid-specific CD8+ T cell (Cap-CD8) elimination of transduced hepatocytes. Hemophilia B patients who develop transient transaminitis and loss of FIX protein may be stabilized with the immune-suppressive (IS) drug prednisolone, but do not all recover lost FIX expression, whereas some patients fail to respond to IS. We developed the first animal model demonstrating Cap-CD8 infiltration and elimination of AAV-transduced hepatocytes of immune-deficient mice. Here, we extend this model to an immune-competent host where Cap-CD8 transfer to AAV2-F9-treated mice significantly reduced circulating and hepatocyte FIX expression. Further, we studied two high-expressing liver tropic AAV2 variants, AAV2-LiA and AAV2-LiC, obtained from a rationally designed capsid library. Unlike AAV2, Cap-CD8 did not initially reduce circulating FIX levels for either variant. However, FIX levels were significantly reduced in AAV2-LiC-F9-treated, but not AAV2-LiA-F9-treated, mice at the study endpoint. Going forward, the immune-competent model may provide an opportunity to induce immunological memory directed against a surrogate AAV capsid antigen and study recall responses following AAV gene transfer.http://www.sciencedirect.com/science/article/pii/S2329050117300591AAV vectorcapsid immunitymouse modelhemophilia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Brett Palaschak Damien Marsic Roland W. Herzog Sergei Zolotukhin David M. Markusic |
spellingShingle |
Brett Palaschak Damien Marsic Roland W. Herzog Sergei Zolotukhin David M. Markusic An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells Molecular Therapy: Methods & Clinical Development AAV vector capsid immunity mouse model hemophilia |
author_facet |
Brett Palaschak Damien Marsic Roland W. Herzog Sergei Zolotukhin David M. Markusic |
author_sort |
Brett Palaschak |
title |
An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells |
title_short |
An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells |
title_full |
An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells |
title_fullStr |
An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells |
title_full_unstemmed |
An Immune-Competent Murine Model to Study Elimination of AAV-Transduced Hepatocytes by Capsid-Specific CD8+ T Cells |
title_sort |
immune-competent murine model to study elimination of aav-transduced hepatocytes by capsid-specific cd8+ t cells |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2017-06-01 |
description |
Multiple independent adeno-associated virus (AAV) gene therapy clinical trials for hemophilia B, utilizing different AAV serotypes, have reported a vector dose-dependent loss of circulating factor IX (FIX) protein associated with capsid-specific CD8+ T cell (Cap-CD8) elimination of transduced hepatocytes. Hemophilia B patients who develop transient transaminitis and loss of FIX protein may be stabilized with the immune-suppressive (IS) drug prednisolone, but do not all recover lost FIX expression, whereas some patients fail to respond to IS. We developed the first animal model demonstrating Cap-CD8 infiltration and elimination of AAV-transduced hepatocytes of immune-deficient mice. Here, we extend this model to an immune-competent host where Cap-CD8 transfer to AAV2-F9-treated mice significantly reduced circulating and hepatocyte FIX expression. Further, we studied two high-expressing liver tropic AAV2 variants, AAV2-LiA and AAV2-LiC, obtained from a rationally designed capsid library. Unlike AAV2, Cap-CD8 did not initially reduce circulating FIX levels for either variant. However, FIX levels were significantly reduced in AAV2-LiC-F9-treated, but not AAV2-LiA-F9-treated, mice at the study endpoint. Going forward, the immune-competent model may provide an opportunity to induce immunological memory directed against a surrogate AAV capsid antigen and study recall responses following AAV gene transfer. |
topic |
AAV vector capsid immunity mouse model hemophilia |
url |
http://www.sciencedirect.com/science/article/pii/S2329050117300591 |
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