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Chai Z, Zhang X, Dobbins AL, et al. Dexamethasone transiently enhances transgene expression in the liver when administered at late phase post long term AAV transduction. Hum Gene Ther. 2021;doi: 10.1089/hum.2021.083.
Chai, Z., Zhang, X., Dobbins, A. L., Samulski, R. J., Merricks, E., Nichols, T. C., & Li, C. (2021). Dexamethasone transiently enhances transgene expression in the liver when administered at late phase post long term AAV transduction. Human gene therapy, . https://doi.org/10.1089/hum.2021.083
Chai, Zheng, et al. "Dexamethasone transiently enhances transgene expression in the liver when administered at late phase post long term AAV transduction." Human gene therapy vol. (2021). doi: https://doi.org/10.1089/hum.2021.083
Chai Z, Zhang X, Dobbins AL, Samulski RJ, Merricks E, Nichols TC, Li C. Dexamethasone transiently enhances transgene expression in the liver when administered at late phase post long term AAV transduction. Hum Gene Ther. 2021 Oct 07; doi: 10.1089/hum.2021.083. Epub 2021 Oct 07. PMID: 34617445.
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Hum Gene Ther. 2021 Oct 07; doi: 10.1089/hum.2021.083. Epub 2021 Oct 07.

Dexamethasone transiently enhances transgene expression in the liver when administered at late phase post long term AAV transduction.

Human gene therapy

Zheng Chai, Xintao Zhang, Amanda L Dobbins, R Jude Samulski, Elizabeth Merricks, Timothy C Nichols, Chengwen Li

Affiliations

  1. University of North Carolina at Chapel Hill Gene Therapy Center, 551785, Chapel Hill, North Carolina, United States; [email protected].
  2. University of North Carolina at Chapel Hill Gene Therapy Center, 551785, Chapel Hill, North Carolina, United States; [email protected].
  3. University of North Carolina at Chapel Hill Gene Therapy Center, 551785, Chapel Hill, North Carolina, United States; [email protected].
  4. University of North Carolina at Chapel Hill Gene Therapy Center, 551785, Chapel Hill, North Carolina, United States.
  5. University of North Carolina at Chapel Hill Department of Pharmacology, 207069, Chapel Hill, North Carolina, United States; [email protected].
  6. University of North Carolina at Chapel Hill Department of Pathology and Laboratory Medicine, 196290, Chapel Hill, North Carolina, United States.
  7. University of North Carolina at Chapel Hill Blood Research Center, Chapel Hill, United States; [email protected].
  8. University of North Carolina at Chapel Hill Blood Research Center, Chapel Hill, United States; [email protected].
  9. University of North Carolina at Chapel Hill Department of Pediatrics, 549964, Chapel Hill, North Carolina, United States.
  10. University of North Carolina Carolina Institute for Developmental Disabilities, 137953, Chapel Hill, North Carolina, United States; [email protected].

PMID: 34617445 DOI: 10.1089/hum.2021.083

Abstract

Glucocorticoids have anti-inflammatory and immunosuppressive functions and have commonly been used for preventing liver toxicity after the systemic application of a high dose of adeno-associated virus (AAV) vector for gene therapy. Clinical studies have reported that glucocorticoids have rescued Factor IX (FIX) expression in hemophilia B patients who showed a reduced FIX expression at 6 to 10 weeks post-AAV vector administration. In this study, we explored whether glucocorticoids could affect transgene expression in AAV targeted livers in animal models. When dexamethasone was applied before AAV9/FIX vector administration in the wild-type C57BL/6 mice, FIX expression was much higher than that of the control mice at any time points. More importantly, FIX expression transiently increased after dexamethasone was administered at week 6 or later post-AAV injection regardless of the various dexamethasone treatments applied. The transient enhancement in transgene expression was observed once there were one to several consecutive dexamethasone treatments completed. A similar result was also achieved in another wild type BALB/c and hemophilia B mice that were treated with AAV9/FIX and dexamethasone. This mechanism study demonstrated that the administration of dexamethasone did not change either AAV genome copy number or transgene expression at the transcription level but transiently decreases IFN-β and TNF-α expression in the livers of mice at a later time after AAV injection. Next, we studied the effect of dexamethasone on late transgene expression in hemophilia B dogs. Dexamethasone was administered 1 year after AAV9/FIX injection. Inconsistent with the results in mice, no significant change of FIX expression was observed in hemophilia B dogs. In summary, the results from this study indicate that dexamethasone may have various effects on transgene expression in AAV transduced livers in different species, which provides valuable information about the rational application of dexamethasone in future clinical studies.

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