transform cultured hepatocytes even with known oncogenic DNA viruses such a adenoviruses or 
SV40. 
Additional support for the safety of transplanting transduced hepatocytes is provided by 
our experiments in animals. We have performed ex vivo gene therapy with retroviral 
transduced hepatocytes into at least 40 rabbits and 25 rats. The animals have been followed up 
to 6 months. During this time we have not observed any tumors or malignancies. 
D. Summary of Risks and Benefits 
The potential benefits of this procedure to FH patients will be to slow the progression of 
atherosclerosis and decrease morbidity and mortality of CAD. Gene therapy would be performed 
in a group of FH patients who have developed advanced CAD on traditional therapies and have a 
relatively poor prognosis. Experiments in an authentic animal model for FH have demonstrated 
the feasibility of achieving substantial and prolonged diminutions of total serum cholesterol as a 
result of gene therapy . We do not expect the improvement in hypercholesterolemia to be 
complete so that we consider this therapy an adjunct to more standard therapies such as 
plasmapheresis, LDL-apheresis, and/or pharmacologic agents. Patients that receive gene 
therapy would resume their normal therapeutic programs 6 weeks later. The development of 
gene therapies is necessary because the currently available forms of treatment are inadequate. 
Most traditional forms of therapy lead to only partial improvements in hypercholesterolemia 
and CAD usually progresses unabated despite intensive therapeutic regimens. 
The potential risks of this therapy are complex. The risks of the surgical procedures 
are relatively well defined and are based on extensive experience in similar clinical situations. 
The hepatocyte infusion is likely to be the most morbid procedure although it is difficult to 
predict these risks because infusion of autologous hepatocytes into humans has never been done. 
Our early experience in nonhuman primates is encouraging. Experience with islet cell 
transplantation in humans suggests that the risk of portal vein thrombosis is less than 4%. The 
risks associated with gene transfer and random integration into the genome are largely unknown 
but are expected to be quite low. 
Recombinant DNA Research, Volume 15 
[195] 
