SiRNA based strategies for inhibition of apoptotic pathways in vivo--analytical and therapeutic implications

Apoptosis is a genetically controlled mechanism of cell death which is important for embryogenesis, metamorphosis, tissue homeostasis and tumor regression of multicellular organisms. In normal cells as well as in transformed cells signals released from the cytoplasm and/or the cell membrane can trigger the activation of caspases which in turn cleave many cellular substrates, leading to the characteristic morphology of apoptosis. Systematic analysis and dissection of apoptotic pathways was obtained by the use of knock out or transgenic organisms, expressing dominant active or negative proteins. The use of antisense oligonucleotides (ASO) for analysis of apoptotic pathways was commonly restricted to cultured cells, because of the low efficacy of ASO in in vivo experiments. In order to investigate the contribution of specific apoptotic pathways in the onset and maintenance of disease in vivo experiments are needed. This approach allows the analysis of apoptotic pathways within their physiological/pathophysiological environment. The combination of recent advances in in vivo gene delivery with siRNA technique for efficient gene silencing provides new, unique possibilities to study apoptotic pathways thereby evaluating new molecular therapeutic strategies in vivo. In this minireview we will focus on the use of RNA interference for analytical and therapeutical suppression of apoptotic pathways in vivo with special consideration of the liver.