Proteasome inhibition is partially effective in attenuating pre-existing immunity against recombinant adeno-associated viral vectors

Pre-existing immunity against adeno-associated virus (AAV) remains a major challenge facing the clinical use of systemic administration of recombinant AAV vectors for the treatment of genetic and acquired diseases using gene therapy. In this study, we evaluated the potential of bortezomib (marketed...

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Bibliographic Details
Published in:PloS one 2012-04, Vol.7 (4), p.e34684-e34684
Main Authors: Karman, Jozsef, Gumlaw, Nathan K, Zhang, Jinhua, Jiang, Ji-Lei, Cheng, Seng H, Zhu, Yunxiang
Format: Article
Language:English
Subjects:
Animals
Antigen presentation
B cells
Biology
Bone marrow
Boronic Acids - pharmacology
Bortezomib
Cancer
Clinical trials
Cytokines - metabolism
Cytotoxicity
Dependovirus - immunology
Disease
Expression vectors
Flow Cytometry
Gene expression
Gene therapy
Genetic disorders
Genetic Vectors - immunology
Hemophilia
Immune response
Immune system
Immunity
Immunity - drug effects
Immunoglobulin G
Immunoglobulins
Immunological memory
Immunosuppressive agents
Immunotherapy
Infections
Inhibition
Laboratory animals
Leukemia
Liver
Lymphocytes B
Lymphocytes T
Male
Medical research
Medical treatment
Medicine
Memory cells
Mice
Multiple myeloma
Organs
Plasma cells
Proteasome Inhibitors
Proteasomes
Proteins
Pyrazines - pharmacology
Rodents
Science
Studies
T cells
Vectors (Biology)
Viruses
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Summary:Pre-existing immunity against adeno-associated virus (AAV) remains a major challenge facing the clinical use of systemic administration of recombinant AAV vectors for the treatment of genetic and acquired diseases using gene therapy. In this study, we evaluated the potential of bortezomib (marketed under trade name Velcade) to abrogate a pre-existing immunity to AAV in mice, thereby allowing subsequent transduction by a recombinant AAV vector of the same serotype. We demonstrate that bortezomib efficiently reduces AAV-specific IgG titres and moderates the cytotoxic T cell response in mice that have a pre-existing immunity to AAV2/8. Significant depletion of AAV2/8-specific IgG-producing plasma cells in secondary lymphoid organs and bone marrow was observed. However, this inhibition of the immune response by bortezomib was insufficient to allow subsequent re-infection with a recombinant AAV vector of a similar serotype. We show that this shortcoming is probably due to the combination of residual antibody levels and the inability of bortezomib to completely deplete the memory B cells that are re-activated in response to a repeated infection with a recombinant AAV vector. Taken together, the results of this study argue for the use of immunosuppressive therapies that target both plasma and memory B cells for the efficient elimination of pre-existing immunity against AAV2/8 vectors.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0034684