Liver Directed Cell Therapy for Inborn Errors of Metabolism

Several excellent animal models are available to establish the principles of liver cell therapy. These animal models include: the Gunn rat model of Crigler-Najjar Syndrome type 1 (73), in which bilirubin-UDP-glucuronosyltransferase (UGT1A1) activity is deficient and unconjugated bilirubin accumulates producing neurotoxicity; Nagase analbuminemic rats (NAR), which exhibit extremely low levels of serum albumin resulting from defective albumin mRNA processing; the Watanabe heritable hyperlipidemic rabbit, which lack cell surface receptors for low-density lipoproteins and models familial hypercholesterolemia (74); the Long-Evans Cinnamon (LEC) rat, an animal model for Wilson's disease (75); the FAH mouse, which models hereditary tyrosinemia type-1 (13,21); and the mdr-2 knockout mice, which model progressive familial intrahepatic cholestasis (76). Mutant animals with diseases of the urea cycle, porphyria, lipidoses, and coagulation disorders are also available (77-80). Similarly, animal models have been identified to study acute or chronic liver failure, cirrhosis and viral hepatitis (63-65,81-83). Of course, type 1 diabetes mellitus can be induced in animals by depleting pancreatic P-cell mass in various ways, including with streptozotocin toxicity.

Transplantation of normal hepatocytes with adequate amounts of liver repopulation can markedly ameliorate metabolic abnormalities in Gunn rats and NAR (73), Watanabe rabbits (74), LEC rats (75), FAH mice (21), mdr-2 mice (76), and lipoproteinemic mice (61). Similarly, primary oval cells isolated from the normal rat liver can differentiate into mature hepatocytes after transplantation into NAR or LEC rats and correct diseases in these animals (84). Of course, these studies indicate that the liver of animals needs to be perturbed for transplanted cells to proliferate, with the exception of animals with chronic ongoing liver damage, as encountered in FAH mice and LEC rats. Early studies in patients have begun to bear out these results in animals. For example, transplantation of genetically modified autologous hepatocytes in patients with familial hypercho-lesterolemia (85) and of allogeneic hepatocytes in patients with ornithine transcarbamylase (OTC) deficiency, a-1-antitrypsin deficiency, or Crigler-Najjar syndrome type 1 (86-88) led to limited therapeutic efficacy but not cures. These results are likely the result of limited liver repopulation.

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