Molecular Genetic Investigation and Therapy for Inborn Errors of Metabolism 
stasis and that the fermentation and absorption of 
propionate may be an important factor regulating 
organic acid homeostasis. 
Basic Methods for Gene Transfer 
We have focused on the liver and the intestines 
as targets for somatic gene therapy. In an ongoing 
collaboration with Savio Woo (HHMI, Baylor Col- 
lege of Medicine) , we have been involved in de- 
veloping a scheme for hepatic gene therapy that 
involves harvesting and cultivating hepatocytes, 
transducing these cells with recombinant retro- 
viral vectors, and returning them to the host via 
hepatocellular transplantation. 
In collaboration with Susan Henning (Depart- 
ment of Pediatrics, Baylor College of Medicine), 
we have developed methods for transducing 
genes into intestinal epithelium. This involves in- 
stilling recombinant retroviruses into isolated 
intestinal segments in the presence of agents to 
increase infectivity, reduce mucus, and increase 
the number of dividing crypt cells. These experi- 
ments demonstrate that it is possible to transduce 
crypt cells, though considerable work remains to 
achieve more efficient transduction. 
Clinical Foundation of Somatic 
Gene Therapy 
We have also begun to establish a clinical foun- 
dation for somatic gene therapy by developing a 
clinical trial of hepatocellular transplantation for 
acute hepatic failure in children. We will use he- 
patic cells transduced with recombinant retrovi- 
rus expressing a marker gene (in collaboration 
with Savio Woo and others at Baylor College of 
Medicine). Hepatocellular transplantation, an es- 
sential of proposed schemes for hepatic gene 
therapy, has never been attempted in humans. We 
are establishing surgical and clinical methods for 
such transplantation. Use of marker genes will 
facilitate assessment of cellular engraftment and 
of techniques for transducing recombinant genes 
into hepatic cells. 
The development of this protocol has focused 
our attention on the myriad clinical issues in- 
volved in human trials, including proper patient 
selection, obtaining meaningful informed con- 
sent, ensuring adequate follow-up, adopting 
methods that are approved for clinical use and 
meet the standards of quality control required for 
clinical practice, satisfying guidelines for con- 
tainment, and involving various health profes- 
sionals and the public in this exciting therapeutic 
frontier. Many of these issues have become re- 
search projects in themselves as we have tried to 
establish a formal basis for clinical trials of gene 
therapy. 
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