HEPATOCELLULAR TRANSPLANTATION AND TARGETING GENETIC MARKERS TO HEPATIC CELLS 
I 
The HCT portion of this protocol has been approved by the IRB conunittees at both BCM 
and TCH. 
Gene transduction. There is considerable benefit to society in the scientifically ' 
rigorous development of methods for HCT and the development of methods for somatic gene I 
therapy for hepatic diseases which would be furthered by assessing the ability of , 
recombinant vectors to mark cells in this protocol. As described above, previous i 
studies in HCT using animal models which have lacked unequivocal markers for the | 
transplanted cells have produced controversial results. The use of transgenic marker* 
genes in animal models was central to critically establishing that HCT could be* 
performed successfully. We believe that the scientific quality of this research is“ 
improved by the application of genetic markers to demonstrate the success of engraftment 
in study subjects. There is considerable benefit to society in the development of 
methods which may be applicable to somatic gene therapy targeted to the liver. The 
detection of transduced genetic material in hepatic cells in vivo in this protocol would 
provide precedents for gene therapy experiments in which normal gene functions would be * 
constituted in autologous cells prior to cellular implantation. f j| 
The presence of the genetic marker in transplanted hepatocytes may provide! 
substantial benefit to certain patients. This benefit will accrue in circumstances 
where decisions about immunosuppression would benefit from information about the state : 
of the engrafted cells. Specifically, if long term clinical improvement is observed a' 
following HCT we would like to determine whether hepatic function is being maintained f:j 
by the transplanted cells or regeneration of host cells. A recent report of auxiliary |)ji 
transplantation by Moritz et al (1990) demonstrated that a heterotopic graft was able f!, 
to provide a "bridge to recovery" in a child with fulminant hepatic failure even though l| 
the auxiliary graft was subsequently lost. We believe one possible outcome of this |i| 
study is that the transplanted cells will provide a "bridge" which will enable host |r- 
cells to recover. If biopsy samples reveal regeneration f the patient's own cells, it ii 
would benefit the patient to discontinue the immunosuppressive therapy intended to f| 
preserve the graft. If examination of biopsy samples shows improvement consistent with |! 
the fraction of cells bearing the genetic marker, then immunosuppression would be pj 
continued. , |i| 
i 
The theoretical risks of gene transfer using retroviral vectors have been assessed fj' 
in animal models and human subjects as described above. Quantitative evaluation of the W| 
risks to study subjects is difficult since no complications have been observed to date, (ji 
Studies performed at the NIH and elsewhere have established that recombinant retroviral ■: 
vectors present no significant risk to the environment or non- subjects (Weingaarten - it| 
formal approval of TIL protocol). We believe the potential risks to the study subjects i 
are small relative to the severity of their disease or the risks associated with the I 
conventional alternative of OLT, The theoretical risks associated with gene transfer t 
are addressed in detail in the responses to "Points To Consider..." and the issues | 
raised by the RAC will be explicitly listed for study participants in the informedM 
consent. The informed consent will emphasize the novel aspects of this research “J 
including the potential risks of recombinant retroviral vectors. 
[800] 
Recombinant DNA Research, Volume 14 
