Division of Gastroenterology & Liver Diseases

Jayanta Roy-Chowdhury, M.B.,B.S.

Dr. Jayanta Roy-Chowdhury

Professor, Department of Medicine (Gastroenterology & Liver Diseases)

Professor, Department of Genetics

Scientific Director, Gene Therapy Facility

 

Professional Interests

Key Words:  Hepatocyte transplantation, Stem cells, gene-therapy

 

During the past decade, liver-directed cell therapy and gene therapy for inherited metabolic disorders has progressed to a point where successful clinical application is in sight. Our current preclinical targets are inherited hyperbilirubinemia (Crigler-Najjar syndrome, CN-1), mucopoly­saccharidosis VII (MPS-VII) and alpha-1 antitrypsin (AAT) deficiency. We have been pursuing several approaches for liver-directed gene therapy as follows.

 Subproject 1.  Hepatocyte-based therapies for genetic liver diseases.  The conventional source for human hepatocytes is livers from deceased allogeneic donors. Hurdles to broad clinical application of this highly promising approach include the scarcity of usable donor organs and the need for prolonged immunosuppression. To overcome these limitations, we are developing methods to abrogate allograft rejection of hepatocytes by transferring into donor hepatocytes ex vivo specific genes derived from the adenoviral DNA that down-regulate  cell surface death receptors, thereby preventing killing by effecter T-cells. In other studies, we are developing methods to induce preferential proliferation of the transplanted hepatocytes by preparative irradiation of the host liver, so that a small number of donor hepatocytes can repopulate the host liver.  Our work has been translated into the first successful hepatocyte allotransplantation in a patient with CN-1. Classic AAT deficiency disease arises from the inheritance of the AAT-Z variant that results from substitution of lysine for glutamate 342.  This mutation alters the folding and biogenesis of the protein, rendering it prone to polymerization and aggregation within the hepatocyte endoplasmic reticulum (ER).  This causes pulmonary emphysema by loss of AAT function. In some patients, accumulation of the misfolded protein causes liver disease as a gain of function. Recently, we have shown that normal hepatocytes transplanted in the livers of mice expressing human AAT-Z spontaneously proliferate, competitively replacing hepatocytes containing globules of PiZ. The mechanism of hepatic repopulation is being investigated in the above models of genetic liver diseases. 

Subproject 2.  Human embryonic and pluripotent stem cells as sources of hepatocytes: As a novel source of hepatocytes, we are generating differentiated hepatocytes by manipulating human embryonic stem cells and induced pluripotential stem cells (iPSCs) in culture from normal individuals and patients. The cells have been used to partially repopulate livers of both immunodeficient mice and immunosuppressed rats. We have shown that human hepatocyte-like cells, derived from ES and iPS cells can reduce serum bilirubin levels after transplantation into UGT1A1-deficient jaundiced Gunn rats (model of Crigler-Najjar syndrome, type 1. Current studies are focused on (1) optimization of disease-specific iPS cell development, (2) differentiation of stem cells to hepatocytes and (3) evaluation of metabolic function after transplantation into animal models of human metabolic diseases.

 Subproject 3.  Gene therapy via recombinant viral vectors and non-viral vehicles: We have developed novel adenoviral vectors that disrupt the costimulatory interaction between antigen-presenting cells and T-lymphocytes and, therefore, can be readministered without stimulation immune response. We are also pursuing ex vivo gene therapy  based on genetic modification of primary or iPSC-derived hepatocytes.  

 

Selected Publications

Recent Publications:

    Basma H, Soto-Gutiérrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Álvarez N, Wong R, Roy-Chowdhury J,  Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ. Differentiation and Transplantation of Human Embryonic Stem Cell-Derived Hepatocytes. Gastroenterology 136:990-9, 2009.

    Wang X, Sarkar DP, Mani P, Steer CJ, Chen Y, Guha C, Chandrasekhar  V, Chaudhuri A, Roy-Chowdhury N, Kren BT, Roy-Chowdhury J. Long-term reduction of jaundice in Gunn rats by non-viral liver-targeted delivery of Sleeping Beauty transposon. Hepatology, in press, 2009.

    Louboutin J-P, Chemasova AA, Marusich E, Roy-Chowdhury J, Strayer DS. Efficient CNS gene delivery by intravenous injection. Nature Methods, 7:905-7, 2010. Pubmed PMID 20953176.

    Ding J, Yannam GR, Roy-Chowdhury N, Hidvegi T, Basma H,  Rennard SI, Wong RJ, Avsar Y, Guha C, Perlmutter DH,   Fox IJ, Roy-Chowdhury J. Spontaneous hepatic repopulation in transgenic mice expressing mutant human alpha 1-anti-trypsin by wildtype donor hepatocytes. J. Clin. Invest. 121(5):1930-4, 2011. Pubmed PMID 21505264.

    Zhou H, Dong X, Kabarriti R, Chen Y, Avsar A, Wang X, Ding J, Liu L, Fox IJ, Roy-Chowdhury J, Roy-Chowdhury N*, Guha C*. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PLoS One, 2012, 7(10): e46775. doi:10.1371/journal.pone.0046775. (*Co-communicating authors).

 

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 523
Bronx, NY 10461

Tel: 718.430.2265
jayanta.roy-chowdhury@einstein.yu.edu

 
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