Recombinant DNA Advisory Committee - 12/1-2/94 
that the observed decrease in serum cholesterol may not be due to gene transfer. Such an effect was not 
considered in the published data. Dr. Motulsky was concerned about the invasive procedure involved in this 
gene therapy protocol such as removing part of the liver and reinfusing the gene-modified liver cells to the 
patients. Dr. Motulsky recommended that ad hoc experts should be included in the review of future protocols 
involving novel strategies in which the RAC may have limited expertise. Dr. Motulsky explained that the 8 
cystic fibrosis (CF) studies have yielded valuable information regarding biochemical and biological evidence of 
corrections. Although toxicity was observed in one patient, the vector dosage was modified, and the subject’s 
symptoms were transient. No subjects have been entered on the RAC-approved studies for Gaucher disease, 
Fanconi anemia, alpha-1 antitrypsin deficiency, rheumatoid arthritis, or peripheral artery diseases. Dr. 
Motulsky noted that there are many groups working on the same disease such as CF; therefore, a coordinated 
effort between investigators would facilitate progress. Dr. Walters noted that there is some evidence of gene 
transfer in bone marrow cells (between 2 and 5% colony forming units) tested at 1 year after transduction of 2 
infants in the SCID-ADA protocol. Dr. Noguchi commented that if there is a limited population of patients, 
more than one of these studies must be synergistic not antagonistic. He was pleased to note that such 
coordination was encouraged by the Cystic Fibrosis Foundation at its annual meetings. Dr. DeLeon asked if 
there is any protocol that has progressed beyond the Phase I stage. Dr. Noguchi responded that there are no 
Phase II studies approved to date. 
Ms. Meyers asked if there is any evidence of long-term gene expression. Dr. Parkman responded that long- 
term expression is not an objective for these CF studies. Persistence of marked normal hematopoietic 
progenitor cells has been demonstrated for up to 18 months in Dr. Brenner’s acute myelogenous leukemia 
patient gene marking study. There is opportunity to learn from these marking studies whether long-term 
expression occurs in adults compared to children. Ms. Meyers was encouraged by the results and asked why 
the SCID-ADA protocol has not been modified to enter additional patients or to eliminate concurrent PEG- 
ADA enzyme replacement therapy. Dr. Parkman said once the long-term persistence in stem cells is 
established, it will be medically appropriate to consider reducing the PEG-ADA dosage. 
Dr. Saha asked if gene therapy efficacy can be assessed in these SCID-ADA patients. Dr. Parkman responded 
that the observed clinical benefits are probably attributed to the synthetic PEG-ADA enzyme replacement. In 
order to definitively establish whether this clinical benefit is due to gene therapy, it is necessary to reduce or 
discontinue the PEG-ADA therapy. Such experimentation poses an ethical dilemma for physicians since they 
are obligated to do no harm to patients. One possible endpoint to assess the contributing effect of gene 
transfer would be to determine whether there is an increase in the number of the circulating T lymphocytes 
bearing the transgene since these cells are of donor origin. Dr. Walters commented that the results need to be 
documented in a scientific publication; there has been anecdotal account of this treatment in Larry 
Thompson’s book, Correcting The Code (Simon & Schuster, New York, 1994). Dr. Chase expressed his 
uneasiness about the inconclusive nature of the experimental design as well as the anecdotal account of the 
study. He stressed the need to have the general public more accurately informed about the outcome of gene 
therapy studies, and the Data Management Report has served this purpose very efficiently. Dr. Saha noted 
that a similar study involving Gaucher disease may cost an additional $1,000 per day for concurrent enzyme 
replacement therapy. 
Dr. DeLeon asked whether efficacy is relevant for a Phase I study. Dr. Noguchi responded that efficacy is not 
the primary endpoint. Dr. Noguchi noted that the parent of one subject demanded concurrent enzyme 
treatment. Ms. Wilson noted that Dr. Blaese’s Data Reporting form stated that if the inserted gene persists 
for 10-12 additional months, PEG-ADA therapy will be cautiously withdrawn, one patient at a time. 
Dr. Anderson suggested that the RAC should request that investigators publish their data in the scientific 
literature. Dr. Ross recommended that investigators should report data in a timely manner. She noted that 
several closed protocols have not submitted data. 
Report on Gene Therapy/HIV-Dr. Straus 
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Recombinant DNA Research, Volume 20 
