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A humanized mouse model for adeno-associated viral gene therapy.

Publication ,  Journal Article
Barzi, M; Chen, T; Gonzalez, TJ; Pankowicz, FP; Oh, SH; Streff, HL; Rosales, A; Ma, Y; Collias, S; Woodfield, SE; Diehl, AM; Vasudevan, SA ...
Published in: Nat Commun
March 4, 2024
Published version (DOI) Link to item

Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg-/-/Rag2-/-/Fah-/-/Aavr-/- (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.

Duke Scholars

Charles Gersbach
Author Charles Gersbach Biomedical Engineering
Anna Mae Diehl
Author Anna Mae Diehl Medicine, Gastroenterology
Aravind Asokan
Author Aravind Asokan Surgery, Surgical Sciences
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Published In

Nat Commun

DOI

10.1038/s41467-024-46017-0

EISSN

2041-1723

Publication Date

March 4, 2024

Volume

15

Issue

1

Start / End Page

1955

Location

England

Related Subject Headings

  • Mice
  • Liver
  • Humans
  • Hepatocytes
  • Genetic Therapy
  • Disease Models, Animal
  • Dependovirus
  • Animals
 

Citation

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MLA
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Barzi, M., Chen, T., Gonzalez, T. J., Pankowicz, F. P., Oh, S. H., Streff, H. L., … Bissig, K.-D. (2024). A humanized mouse model for adeno-associated viral gene therapy. Nat Commun, 15(1), 1955. https://doi.org/10.1038/s41467-024-46017-0
Barzi, Mercedes, Tong Chen, Trevor J. Gonzalez, Francis P. Pankowicz, Seh Hoon Oh, Helen L. Streff, Alan Rosales, et al. “A humanized mouse model for adeno-associated viral gene therapy.” Nat Commun 15, no. 1 (March 4, 2024): 1955. https://doi.org/10.1038/s41467-024-46017-0.
Barzi M, Chen T, Gonzalez TJ, Pankowicz FP, Oh SH, Streff HL, et al. A humanized mouse model for adeno-associated viral gene therapy. Nat Commun. 2024 Mar 4;15(1):1955.
Barzi, Mercedes, et al. “A humanized mouse model for adeno-associated viral gene therapy.” Nat Commun, vol. 15, no. 1, Mar. 2024, p. 1955. Pubmed, doi:10.1038/s41467-024-46017-0.
Barzi M, Chen T, Gonzalez TJ, Pankowicz FP, Oh SH, Streff HL, Rosales A, Ma Y, Collias S, Woodfield SE, Diehl AM, Vasudevan SA, Galvan TN, Goss J, Gersbach CA, Bissig-Choisat B, Asokan A, Bissig K-D. A humanized mouse model for adeno-associated viral gene therapy. Nat Commun. 2024 Mar 4;15(1):1955.

Published In

Nat Commun

DOI

10.1038/s41467-024-46017-0

EISSN

2041-1723

Publication Date

March 4, 2024

Volume

15

Issue

1

Start / End Page

1955

Location

England

Related Subject Headings

  • Mice
  • Liver
  • Humans
  • Hepatocytes
  • Genetic Therapy
  • Disease Models, Animal
  • Dependovirus
  • Animals