Conclusion: Anchoring IFNα to ApoA-I prolongs the half-life of IFNα and promotes targeting to the liver. Importantly, the fusion protein shows increased immunostimulatory properties this website and lower hematological toxicity. (HEPATOLOGY 2011;) Interferon alpha (IFNα)

is a key component of the innate immune system and plays an essential role in the defense against viral infections. In addition to direct antiviral effects,1 IFNα displays antiproliferative,2 proapoptotic,3 immunomodulatory,4 and antifibrogenic activities.5 Recombinant IFNα is widely employed for the treatment of chronic viral hepatitis and neoplastic diseases6, 7 but a number of side effects limit its use. Alterations in the hematopoietic system, mainly thrombocytopenia and leukopenia, are among the most important unwanted consequences of this therapy. As a result, IFNα is not indicated in patients with low platelet or leukocyte counts, which is the case with many subjects with advanced chronic viral infection.8 Another limitation of IFNα-based therapies is its short half-life in plasma. The therapeutic activity of IFNα in chronic viral hepatitis is enhanced

by formulations that prolong its persistence in the circulation, selleck compound including pegylation of the molecule (PEG-IFNα)9 or its fusion with stabilizing proteins such as albumin.10 BCKDHA However, these modifications of the IFNα molecule do not provide

hepatic tropism, a property that would be desirable in the treatment of liver diseases such as chronic viral hepatitis. We therefore designed an IFNα fusion protein that combines both increased half-life and liver tropism. We selected apolipoprotein A-I (ApoA-I), the main protein component of high-density lipoproteins (HDLs), as the stabilizing and targeting moiety. HDLs are generated in the liver and remove cholesterol from peripheral tissues for delivery to hepatocytes.11 Consistent with the key role of HDLs in the reverse cholesterol transport, it has been shown that ApoA-I accumulates preferentially in the liver following its systemic administration.16 Scavenger receptor class B type I (SR-BI) plays a crucial role in HDL biology.13 After binding to SR-BI, HDLs mediate the uptake of cholesteryl esters and phospholipids from the cells and promote cytoprotective functions by imperfectly understood mechanisms involving multiple interactions between HDLs (lipid or protein moiety) and cell surface receptors.14 SR-BI is expressed at low levels in a wide variety of cells, and at high levels in the liver, adrenal glands, ovaries, testis, intestinal cells, phagocytes, and endothelial cells.11, 15 The present work evaluates the properties of a new fusion protein designed to increase the half-life of IFNα and to target the liver.