by Mary Ann Liebert, Inc
Figure 1. The long-term expression of hFIX in wild-type C57BL/6 mice pretreated with dexamethasone. (A) The schematic of the dexamethasone and AAV9/hFIX administrations and serum collection from blood. Dexamethasone (0.2 mg/mouse) or PBS was injected 2 h before 1 × 1010 vg of AAV9/hFIX vectors per mouse were administered through the retro-orbital vein. The same dose of dexamethasone was administered daily for the next 6 days. The sera were collected at 1, 2, and 6 weeks (W1, W2, and W6), separately. (B) The hFIX expression was measured by human FIX specific ELISA assay. The data represent the average and SD from five mice. The asterisk indicates the significant difference (***p < 0.001 and **p < 0.01). AAV9, adeno-associated virus 9; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; SD, standard deviation; vg, vector genomes. Credit: DOI: 10.1089/hum.2021.083
Dexamethasone, a glucocorticoid with anti-inflammatory and immunosuppressive effects, can transiently increase the expression of therapeutic genes delivered using adeno-associated virus (AAV) vectors. A new study, which showed that dexamethasone administration at a late time point could increase transgene expression from AAV9 vector transduced liver in mice, was published in the peer-reviewed journal Human Gene Therapy.
“Corticosteroids like dexamethasone, methylprednisolone and prednisone are frequently used in AAV-based human gene therapy protocols, but the optimal timing of such therapy has not been thoroughly studied,” says Human Gene Therapy Editor-in-Chief Terence R. Flotte, MD. “This paper provides an interesting insight into the potential effects of short-duration steroid therapy.”
Chengwen Li, Ph.D. and coauthors from the University of North Carolina at Chapel Hill demonstrated that the increased transgene expression was not dependent on the duration or time point of dexamethasone administration after AAV injection. The researchers did not report increased transgene expression in hemophilia dogs treated with dexamethasone after AAV gene therapy.
“These results provided valuable information to design an effective approach for application of dexamethasone in future clinical studies with AAV vector liver targeted gene therapy, such as short term and intermittent administration of steroids,” state the investigators. “This may decrease the toxicities from long term application of steroids and also avoid liver damage from high doses of AAV vector seen in clinical trials.”
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