Hepatocellular Therapy for Hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disease resulting from mutations in the LKLrecptor. Markedly elevated serum cholesterol levels lead to heart disease in FH, and the availablepharmacological therapy is often not adequate to reduce cholesterol to safe levels. Hepatocytetransplantation has the capacity to be used as a therapy for hypercholesterolemia, but the problem ofrejection of foreign cells by the immune system of the recipient has hampered its development. We willtransplant animal liver cells as a cellular therapeutic for the treatment of FH. To overcome the problemof immediate rejection, the major histocompatibility antigens (MHC class I) of the hepatocytes will bereacted with monoclonal antibodies that have been shown to prevent recognition and subsequent killingof the cells by the recipient's immune system. In Phase I, the efficacy of the method will be tested inthe Watanabe rabbit, an animal model for homozygous FH. Donor porcine hepatocytes will be treatedwith f (ab1)2 fragments of swine class I antibodies and infused into the portal vein of the rabbits fordelivery to the liver where the cells will engraft. The cholesterol levels of the animals will be monitoredafter transplantation to assess the effectiveness of treatment. If efficacy is proven in the hypercholes-terolemic rabbits, this new technology will be tested in primates and in humans for the treatment of FH.