Recombinant DNA Advisory Committee - 10/7-8/91 
the virus and the cells post-transfection, and clarification of the stopping rules. A revised 
consent document was also requested. 
Dr. Doi said that some of the strong points of the protocol were as follows. The 
preclinical results with the Watanabe rabbit model seemed very promising. The 
recombinant autologous hepatocytes were associated with the 30-40% decrease in serum 
cholesterol which persisted for about four months. No immune response to the 
recombinant LDL receptor was noted. Although there was a higher than normal level of 
LDL receptor expression, it did not seem to affect the physiology of the cells. There was 
relatively little, or no, rejection of infected allogeneic hepatocytes, which will allow long- 
term treatment in the absence of immunosuppressive therapy. The investigator worked 
out some aspects of the experimental design with a single baboon. The technical aspects 
of partial hepatectomy and catheter placement seem to work well with no postoperative 
difficulties. There are two kinds of patients, those who are homozygous for the 
abnormal LDL receptor genes and those who are heterozygous. The homozygous 
patients usually die at about age 12; so it is critical to treat these patients. In summary, 
this is a well thought-out protocol based on solid preclinical data and that the probability 
of success seems high. 
Mr. Capron noted that patients are to be brought to the University of Michigan to 
participate in this protocol from around the country. He asked whether the information 
that accompanies the consent form is provided at the time that they are already in 
Michigan. He asked for clarification of the timing of the information, the timing of the 
consent process, the patient's transportation to Michigan, and the availability of other 
treatments at the University of Michigan in addition to gene therapy. The Points to 
Consider submitted by the investigator to the RAC insist that subjects not withdraw after 
the liver is resected but before the cells have been reinfused. The reason for concern is 
that the patient would have taken a surgical risk and received no benefit. Clearly this is 
a paternalistic judgement on the part of the researchers. If someone chooses to 
withdraw at this point, he/she must be free to withdraw. He expressed concern, as he 
had at the subcommittee meeting, that this research, which is still at a very early stage of 
gene therapy, should not be performed with children. This is a disease which does 
express itself in children but also expresses itself in adults. The committee has to 
recognize the fact that this remains experimental, and the researchers say there is only a 
small possibility that there will be any benefits. This is a learning process. Learn first 
with people who can consent to participate in that context. If children are going to be 
treated, older children should be asked to sign the consent form because it is not 
appropriate to have an older child participate solely on parental permission. The data 
from the protocol indicates that 25% of the patients die by the age of 11. However, 
there are patients who are critically ill and would be suitable as subjects who are 18 and 
over. The age of consent in most states is 18 years. 
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Recombinant DNA Research, Volume 15 
