Development of a Clinical Protocol for Hepatic Gene Transfer: Lessons Learned in Preclinical Studies View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

1993-04

AUTHORS

Fred D Ledley, Mark R Adams, Humberto E Soriano, Gretchen Darlington, Milton Finegold, Robert Lanford, Dee Carey, Dorothy Lewis, Patricia A Baley, Steve Rothenberg, Mark Kay, Mary Brandt, Robert Moen, W French Anderson, Peter Whitington, William Pokorny, Savio L C Woo

ABSTRACT

ABSTRACT: Strategies for hepatic gene therapy have been proposed that involve isolation of primary hepatocytes and introduction of recombinant genes into these cells in culture, followed by autologous hepatocellular transplantation (HCT). Consideration of clinical applications requires data suggesting that HCT can be performed safely in human subjects in addition to data indicating that recombinant gene expression can reverse a disease process. This report describes preclinical studies that underlie a clinical trial of HCT in which hepatocytes would be labeled with a marker gene to facilitate assessment of engraftment in the recipient. Human hepatocytes were harvested from liver segments preserved in Belzar's solution and transduced with an amphotropic retroviral vector carrying a recombinant marker gene (neomycin phosphotransferase II). Human hepatocytes were recovered from monolayer culture, stained with the fluorescent dye 1,1′-dioctadecyl-3,3,3,3′-tetra-methylindo-carbocyanine perchlorate (DiI) and transplanted into severe combined immunodeficient mice by splenic injection. Engrafted hepatocytes were identified in the liver and spleen of severe combined immunodeficient mice but not immunocompetent controls. Two large animal models of HCT are described. In a dog model, neomycin phosphotransferase II-containing hepatocytes were identified in the liver 7 wk after transplantation. In a baboon model, autologous HCT with DiI-stained cells demonstrated that transplanted cells assume a normal morphology and constitute up to 5% of hepatocytes. These data demonstrate transduction and transplantation of human hepatocytes and the feasibility of HCT in large animals. On the basis of these studies, the proposed clinical trial for gene transfer and transplantation in human subjects has been approved by the National Institutes of Health and the Food and Drug Administration. These studies illustrate the nature and extent of preclinical data required to gain approval for clinical trials involving gene transfer into human subjects. These data also illustrate the limitations of existing methods that may be used for hepatic gene therapy in the future. More... »

PAGES

313-320

References to SciGraph publications

  • 1991-11. Towards liver-directed gene therapy: Retrovirus-mediated gene transfer into human hepatocytes in SOMATIC CELL AND MOLECULAR GENETICS
  • 1990. Clinical Application of Somatic Gene Therapy in Inborn Errors of Metabolism in CARBOHYDRATE AND GLYCOPROTEIN METABOLISM; MATERNAL PHENYLKETONURIA
  • 1992-06. Human gene therapy comes of age in NATURE
  • 1989-05. Gene expression in implanted rat hepatocytes following retroviral-mediated gene transfer in SOMATIC CELL AND MOLECULAR GENETICS
  • Journal

    TITLE

    Pediatric Research

    ISSUE

    4

    VOLUME

    33

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1203/00006450-199304000-00001

    DOI

    http://dx.doi.org/10.1203/00006450-199304000-00001

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1001088999

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/8386832


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