Our long-term objective is to develop safe and efficient methods for liver-directed gene therapy for genetic disorders of hepatic metabolism, using inherited jaundice due to bilirubin-uridinediphospho-glucuronate glucuronosyltransferase (bilirubin-UGT) deficiency as a model target. Absence of hepatic bilirubin-UGT activity leads to accumulation of the bilirubin in plasma and consequent brain damage, resulting in the potentially lethal Crigler-Najjar syndrome type I (CN-I). Currently, liver transplantation is the only definitive therapy. Gunn rats, the animal model for CN-I, will be used for these studies. During the last four years, both viral and non-viral vehicles for delivery of normal human bilirubin-UGT genes to Gunn rat liver were devised and tested. In this continuation application, two strategies for correcting hepatic bilirubin-UGT deficiency in vivo will be pursued. In the first approach, recombinant viral vectors will be used to substitute hepatic bilirubin-UGT by delivering a normal gene. Recombinant adenoviruses are very efficient in transferring genes into the liver in vivo, but the transgene expression is transient because the virus is episomal and the host immune response precludes its repeated administration. Three methods for specific tolerization of the host to adenoviral antigens, developed in our laboratory, show promise for long-term adenovirus- mediated gene therapy without immunosuppression. To refine these methods for future clinical application, the mechanisms by which they induce specific tolerance will be elucidated. In addition, a much less immunogenic vector, based on the SV40 virus, will be developed and tested. The second approach will utilize RNA/DNA chimeric molecules to repair the genetic lesion in Gunn rats, using our highly efficient vectors for liver-specific nucleic acid delivery by receptor-mediated endocytosis. The gene transfer efficiency will be assessed by molecular, enzymatic and metabolic studies. Successful completion of these studies will provide a basis for gene therapies for CN-I and other inherited metabolic disorders, such as deficiency of alpha1-antitrypsin and urea cycle enzymes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Doo, Edward
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Chen, Yong; Li, Yanfeng; Wang, Xia et al. (2015) Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes. Stem Cell Reports 5:22-30
Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro et al. (2014) A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. Int J Radiat Oncol Biol Phys 88:404-411
Zhou, Hongchao; Dong, Xinyuan; Kabarriti, Rafi et al. (2012) Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One 7:e46775
Wang, Xia; Mani, Prashant; Sarkar, Debi P et al. (2009) Ex vivo gene transfer into hepatocytes. Methods Mol Biol 481:117-40
Yamanouchi, Kosho; Zhou, Hongchao; Roy-Chowdhury, Namita et al. (2009) Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology 49:258-67
Wang, Xia; Sarkar, Debi P; Mani, Prashant et al. (2009) Long-term reduction of jaundice in Gunn rats by nonviral liver-targeted delivery of Sleeping Beauty transposon. Hepatology 50:815-24
Jiang, Jinlan; Salido, Eduardo C; Guha, Chandan et al. (2008) Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1. Transplantation 85:1253-60
Kawashita, Yujo; Guha, Chandan; Moitra, Rituparna et al. (2008) Hepatic repopulation with stably transduced conditionally immortalized hepatocytes in the Gunn rat. J Hepatol 49:99-106
Mashalova, Elena V; Guha, Chandan; Roy-Chowdhury, Namita et al. (2007) Prevention of hepatocyte allograft rejection in rats by transferring adenoviral early region 3 genes into donor cells. Hepatology 45:755-66
Salido, Eduardo C; Li, Xiao M; Lu, Yang et al. (2006) Alanine-glyoxylate aminotransferase-deficient mice, a model for primary hyperoxaluria that responds to adenoviral gene transfer. Proc Natl Acad Sci U S A 103:18249-54

Showing the most recent 10 out of 75 publications