Glucocorticoids could compromise the therapeutic effect of AAV gene therapyPublished: March 12, 2019
A research study has identified the link between systemic glucocorticoid levels and the efficacy of AAV-mediated transgene expression. The study highlights the need in assessing glucocorticoid requirements in patients when designing clinical trials, as the presence of glucocorticoids could affect vector transduction efficacy and compromise therapeutic effect.
Glucocorticoids is one of the commonly prescribed drugs for anti-inflammation, immunosuppression and for enhancing vascular permeability. It is also used to prevent liver toxicity in patients when systemically administering adeno-associated virus (AAV) vectors for central nervous system diseases and muscular disorders.
In the present study published in Human Gene Therapy, Prof. Chengwen Li and team at the University of Pittsburgh’s Gene Therapy Center investigated the impact of dexamethasone, a glucocorticoid, on AAV vascular permeability and therapeutic efficacy after intravenous injection.
The study showed that systemically administering AAV9 (the AAV serotype most commonly used for central nervous system disorders as it can cross the blood brain barrier) at a low dose into mice already treated with dexamethasone did not affect the transduction and vector biodistribution in most tissues, other than the liver and the heart, when compared to control mice.
However, administering a high dose of the vector resulted in significant reduction of both the transgene expression and the AAV vector genome copy number in majority of the murine tissues. Interestingly, transduction was not affected when dexamethasone was given 2 hours after AAV vector injection.
The study also showed that AAV virus clearance in the blood was inversely related to the dexamethasone levels; higher the glucocorticoid, lower the virus clearance and vice versa. Dexamethasone inhibited AAV9 vascular permeability.
Findings from the study highlight the importance of assessing glucocorticoid requirement when designing clinical studies, as it could directly affect vector transduction efficacy and compromise the therapeutic effect.
Source: Optimization of Dexamethasone Administration for Maintaining Global Transduction Efficacy of Adeno-Associated Virus Serotype 9. DOI