Recombinant DNA Advisory Committee - 12/3-4/92 
The objective of this protocol is to genetically correct a limited number of autologous 
hepatocytes and reinfuse these corrected cells back into the patient. On day 0, the left 
lateral segment of the liver is resected and a Pittman style catheter is inserted into the 
inferior mesenteric vein that feeds the portal circulation. Hepatocytes are isolated from 
the resected portion of the patient's liver and exposed to the recombinant retrovirus for 
2 days. Within 72 hours following surgery, these transduced cells are reinfused into the 
catheter. 
Dr. Wilson summarized the results of the baboon toxicity studies. Three large baboons 
underwent the aforementioned procedure with the same retrovirus vector proposed for 
the human trials. These animals have been followed for IVi years. All 3 of these 
animals have a normal clinical profile. Serum chemistries and hematologies have also 
been performed and are normal except for a transient increase in liver enzyme tests at 
the time of resection. 
In situ hybridization has been performed on liver sections from these animals to 
determine if the transduced cells and gene expression have persisted. Although there is 
some variability between biopsy specimens, results indicate that the promoter is 
functional for the duration of the animal experiment and that the transduced cells 
persist. Since these animals did not have any defect in their LDL receptor gene, the 
effect on serum cholesterol could not be monitored. 
The human clinical protocol was approved for 3 patients with homozygous FH. 
Although the study was approved for patients of any age, the RAC suggested that an 
adult should be first patient to receive this treatment. This patient was required to have 
documented coronary artery disease, acceptable surgical risks, and no liver pathology. 
The first patient enrolled in this protocol was a 29 year old female from Quebec, 
Canada. The French Canadian population has an extremely high concentration of 
patients with FH, most of whose genotypes are known. This patient was a homozygote 
with two defective alleles, both of which had a tryptophane/glycine amino acid 
substitution at position 66 which resulted in a substantial binding defect. This patient 
had 2 brothers die from coronary artery disease at ages 20 and 26. The patient had a 
total serum cholesterol of 550 milligrams per deciliter due to an elevation of LDL, a 
myocardial infarction at 16 years of age, and a coronary artery bypass. At the time of 
evaluation, one the patient's bypasses had failed and there was a lesion in the left main 
coronary artery. 
At the time of surgery, 250 grams of her left lateral liver lobe was resected. The liver 
was perfused according to the protocol and 3 x 10 9 viable cells were obtained. These 
cells were plated onto 800 10 centimeter dishes. After 48 hours, the cells were 
transduced and then harvested. A total of 2 x 10 9 cells were recovered and infused in 3 
separate aliquots. Each aliquot was examined for gross contamination, assayed for the 
Recombinant DNA Research, Volume 16 
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