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Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease.

Publication ,  Journal Article
Choi, SJ; Yi, JS; Lim, J-A; Tedder, TF; Koeberl, DD; Jeck, W; Desai, AK; Rosenberg, A; Sun, B; Kishnani, PS
Published in: J Gene Med
August 2023

BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice. METHODS: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood. RESULTS: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19+ B220+ B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration. CONCLUSIONS: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector.

Duke Scholars

Published In

J Gene Med

DOI

EISSN

1521-2254

Publication Date

August 2023

Volume

25

Issue

8

Start / End Page

e3509

Location

England

Related Subject Headings

  • Retreatment
  • Mice
  • Humans
  • Glycogen Storage Disease Type II
  • Genetic Vectors
  • Dependovirus
  • Capsid
  • Bortezomib
  • Biotechnology
  • Antibodies, Viral
 

Citation

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Choi, S. J., Yi, J. S., Lim, J.-A., Tedder, T. F., Koeberl, D. D., Jeck, W., … Kishnani, P. S. (2023). Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease. J Gene Med, 25(8), e3509. https://doi.org/10.1002/jgm.3509
Choi, Su Jin, John S. Yi, Jeong-A Lim, Thomas F. Tedder, Dwight D. Koeberl, William Jeck, Ankit K. Desai, Amy Rosenberg, Baodong Sun, and Priya S. Kishnani. “Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease.J Gene Med 25, no. 8 (August 2023): e3509. https://doi.org/10.1002/jgm.3509.
Choi SJ, Yi JS, Lim J-A, Tedder TF, Koeberl DD, Jeck W, Desai AK, Rosenberg A, Sun B, Kishnani PS. Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease. J Gene Med. 2023 Aug;25(8):e3509.
Journal cover image

Published In

J Gene Med

DOI

EISSN

1521-2254

Publication Date

August 2023

Volume

25

Issue

8

Start / End Page

e3509

Location

England

Related Subject Headings

  • Retreatment
  • Mice
  • Humans
  • Glycogen Storage Disease Type II
  • Genetic Vectors
  • Dependovirus
  • Capsid
  • Bortezomib
  • Biotechnology
  • Antibodies, Viral