Figure 1.

Cell-Type-Specific Targeting Approaches

The drawing shows a schematic reproduction of a liver sinusoid. Liver sinusoidal endothelial cells (LSECs) are cells delineating the hepatic sinusoids. Hepatocyes are separated from endothelial cells by the space of Disse. Stellate cells (SCs) are contained in the space of Disse. On the side facing the bloodstream are found hepatic macrophages, also known as Kupffer cells (KCs), in tight contact with LSECs, and dendritic cells (DCs). Liver-directed gene transfer can be achieved using vector containing cell-type-specific promoter, such as albumin (Alb), Transthyretin (TTR), human alpha antitrypsin (hAAT) promoters for hepatocytes, and ICAM2, Flk1, Tie2, and VEC for endothelial cells. Envelopes of viral vectors can be modified to restrict vector entry to specific cell types, such as the GP64 glycoprotein from baculovirus and hepatitis B virus envelope (HBVE) for hepatocyte transductional targeting. The specificity of transgene expression can be further increased using target sequences with perfect complementarity to cell-specific microRNA (miRT), such as miRT-122 for hepatocytes, miRT-126 for endothelial cells, or miRT-142-3p and miRT-155 for hematopoietic cells, and specifically suppressing the transgene expression in defined cell types without affecting the expression in other cells. ICAM2, intercellular adhesion molecule 2; Flk1, fetal liver kinase 1, the VEGF receptor; Tie2, angiopoietin receptor; VEC, VE-cadherin.