Human Gene Therapy Subcommittee - July 29-30, 1991 
months to be produced. 
Dr. Epstein asked if a 15% reduction of serum cholesterol is meaningful, i.e., a 
reduction from 850 mg/ml to 750 mg/ml or 700 mg/ml. Dr. Wilson replied that he 
proposes to convert a null to a partial deficiency. Dr. Epstein asked if Dr. Wilson had 
enough preclinical data on which to proceed to human trials. Dr. Wilson replied that 
he has systematically achieved a relevant endpoint in his animal model with respect to 
potential efficacy for this inherited disease. Dr. Wilson stated that this conclusion is 
based on these experiments, as well as experiments in other animal systems and 
cultured human hepatocytes. 
Dr. Kelley asked if an expression of the LDL receptor gene in patients after treatment, 
would increase the likelihood that the patients may be rendered more sensitive to 
subsequent pharmacologic therapy. Dr. Wilson said the problem with pharmacologic 
therapy is that it is often based on modulation of the endogenous receptor, primarily at 
the transcriptional level, and the gene to be supplied in the treatment does not have 
the correct transcriptional elements. However, data indicate that there is a 
translational component to this modulation. If so, then pharmacological approaches 
could be used to up-regulate the new receptor gene in these patients. 
Dr. Leventhal said a survival graph of the patients is needed, as well as a good natural 
history data collection system. If the three patients proposed to be treated live to be 
20, it is not clear whether this is a result of the treatment or an expected outcome 
based on their natural history. 
Dr. Parkman asked about the stable efficiency of reintroduced autologous cells in the 
rabbit experiments. Dr. Wilson replied that in situ RNA hybridization data for the 
Watanabe rabbit liver tissue shows that approximately 1% of the liver cells introduced 
are expressing the LDL receptor gene. 
Dr. Mclvor said the endpoint of the treatment should be more than an assessment of 
clinical benefit. It would be meaningful to determine whether the hepatocytes have 
been efficiently transduced and whether these transduced hepatocytes are actually in 
the liver. He asked for a description of the assays that are going to be performed on 
liver biopsies. Dr. Wilson replied that in situ RNA hybridizations will be performed 
along with DNA and RNA polymerase chain reaction (PCR). 
Dr. D. Miller asked why Dr. Wilson had injected the cells into the spleen in the animal 
model if he plans to inject the cells into the portal vein in a human patients. Animal 
experiments should be identical to those being proposed for humans. The vector and 
the route of administration to be used in patients should be tested in the Watanabe 
rabbit model. 
Recombinant DNA Research, Volume 14 
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