HEPATOCELLULAR TRANSPLANTATION AND TARGETING GENETIC MARKERS TO HEPATIC CELLS 
I. Issues in proposing gene transfer in hximan subjects. r 
There has been extensive public and scientific debate over the propriety and ethics R 
of gene transfer in humans and the potential for somatic gene therapy (Friedmann, 1983, fl 
1989; Fletcher, 1985; Anderson, 1984; Friedman and Roblin, 1972; Anderson and Fletcher, fi 
1980). Despite the sometimes rancorous debate, no governmental or religious study in 
this country has raised objections to gene therapy involving somatic cells as long as n 
i) the intent of the research is therapeutic; ii) there is no risk to the environment |i 
or non-subjects; iii) germline therapy is not involved; iv) the legal, moral, and 
spiritual prerogatives of the subjects are protected; and v) and principles of fairness, p 
privacy, confidentiality, and non-discrimination are observed (recent reviews: Nelson, 5 
1990; Murray, 1990; Fletcher, 1990). Many studies have concluded that somatic gene i 
therapy is ethically no different than transplantation of organs, cells, or artificial 
devises to alleviate human suffering (OTA, 1984) . Somatic gene therapy is fundamentally i 
allopathic in nature and distinct from eugenics (Ledley, 1987c). In principle, it is F 
no different than the replacement of a failing organ, limb, or function with a F 
heterologous or artificial graft. 
Because of the widespread professional and public concern about gene transfer in 
humans and the potential for somatic gene therapy, a detailed review process has been ' 
established for the evaluation of protocols. These rules and regulations are detailed |' 
in a document entitled "Points To Consider in the Design and Submission of Human 
Somatic-Cell Gene Therapy Protocols" promulgated by the RAC of the National Institutes > 
of Health (Recombinant DNA Advisory Committee, 1989). While the present protocol does ' 
not represent "somatic-cell gene therapy” , the use of gene transfer to mark hepatocytes i 
requires that this protocol proceed through the channels outlined in the "Points To I 
Consider , , . " . 1 ' 
f 
J. Precedents and implications of the present work. j 
I' 
The present protocol is primarily intended to assess the feasibility and therapeutic | 
efficacy of HCT in human subjects. HCT represents a novel surgical procedure for which [ 
there is extensive animal precedent. This portion of the proposal embodies a ! 
significant therapeutic potential for study subjects, raises no unique issues for the > 
IRB, and would not normally be submitted to the NIH for additional review. This portion 
of the protocol could be technically performed independently of the experiments | 
involving gene transfer. We believe, however, that the scientific quality of this ; 
investigation and the likelihood of acquiring verifiable data and "generalizable ' 
knowledge" will be enhanced by the ability to specifically assay engraftment of 
transplanted cells. ' 
We recognize that methods for gene transfer into hepatocytes have been incompletely 
tested in animal models. We believe that the proposition of therapeutic, clinical 
trials of HCT provides a unique opportunity to assess the applicability of existing 
methods for gene transfer into hepatic cells. More importantly, we beleive that the use 
of gene transfer enhances the probability of performing these experiments in a rigorous 
and verifiable manner. 
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Recombinant DNA Research, Volume 14 
