Targeting Kupffer cells with antisense oligonucleotides.

Abstract

During proinflammatory reactions such as endotoxemia, ischemia-reperfusion and immune reactions, excessive amounts of cytokines and prostanoids are released resulting in liver injury. In the liver, Kupffer cells are the primary source of cytokines and prostanoids. Obliteration of Kupffer cells prevents experimentally-induced liver damage, suggesting a major role for Kupffer in the pathogenesis of liver diseases. Pretreatment of experimental animals with antibodies directed against cytokines such as tumor necrosis alpha (TNF-alpha) prevented experimentally-induced liver damage. In recent years, antisense oligonucleotides (ASOs) directed against specific mRNAs have been tested as an alternative therapy to control the excessive production of inflammatory peptides. Although ASOs have great potential against gene expression, their design, in vivo delivery and stability, have posed significant challenges. Computer-aided configurational analysis and identification of viable motifs (GGGA) on the pre-mRNA transcripts have, in part, alleviated the problems in designing effective ASOs. However, the major challenge involves the in vivo delivery of an ASO to the target tissue. Additionally, it is critical that once taken up by the cells, the ASO is able to survive the lysosomal barrier and enter the cytoplasm. Anionic liposomes and lactosylated low-density lipoproteins (LDL) have been successively used as adjuvants for delivery of ASOs to Kupffer cells. In particular, pH-sensitive liposomes have shown great promise as delivering vehicles to target Kupffer cells. In summary, although ASOs are emerging as a new class of drugs against Kupffer cell-derived pro-inflammatory molecules, in vivo delivery still remains a challenge. pH-sensitive liposomes and LDL-based delivery systems show significant promise for specifically targeting Kupffer cells.