Understanding the contribution of gene function in distinct organ systems to the pathogenesis
of human diseases in biomedical research requires modifying gene expression through
the generation of gain- and loss-of-function phenotypes in model organisms, for instance,
the mouse. However, methods to modify both germline and somatic genomes have important
limitations that prevent easy, strong, and stable expression of transgenes. For instance,
while the liver is remarkably easy to target, nucleic acids introduced to modify the
genome of hepatocytes are rapidly lost, or the transgene expression they mediate becomes
inhibited due to the action of effector pathways for the elimination of exogenous
DNA. Novel methods are required to overcome these challenges, and here we develop
a somatic gene delivery technology enabling long-lasting high-level transgene expression
in the entire hepatocyte population of mice.
