Inflammation promotes the loss of adeno-associated virus-mediated transgene expression in mouse liver.

ABSTRACT:

Background & aims

Non-self transgenes delivered to mouse liver via adeno-associated virus (AAV) are expressed stably due to the induction of immune tolerance. However, such transgene expression has been reported to be lost in higher-order primates. We investigated whether inflammatory processes, which likely differ between species, impact the stability of transgene expression.

Methods

We developed a mouse model that mimics a scenario in which a subject that has received hepatic AAV-mediated gene transfer develops subsequent, vector-unrelated, systemic inflammation.

Results

Inflammation eliminated previously stable expression of transgenes delivered by AAV; the limited tissue destruction and persistence of AAV genomes implicated pathways besides the cytotoxic T-cell response. Tumor necrosis factor-a down-regulated expression of the transgene from the AAV, indicating a role for similar inflammatory cytokines in such loss of transgene expression.

Conclusions

Inflammation can block AAV-mediated expression of transgenes in mouse liver. The presence of inflammation might therefore affect hepatic expression of transgenes from viral vectors in humans.

SUBMITTER: Breous E 

PROVIDER: S-EPMC3269906 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature