Recombinant DMA Advisory Committee - 3/3-4/94 
percentage of transduced epithelial cells. As compared with previously approved cystic 
fibrosis protocols, the preclinical animal studies of the present protocol are inadequate. 
Dr. Parkman recommended that the investigators should be required to provide 
additional data demonstrating the frequency of transduction in both bronchial and nasal 
mucosal cells in a preclinical animal model. 
Review-Dr. Miller (presented by Dr. Parkman) 
Dr. Miller's written comments stated that this protocol employs a non-viral plasmid DNA 
vector which does not pose any significant risk from a recombinant DNA aspect. The 
Biosafety Level (BL) 2 containment, which was recommended by the Institutional 
Biosafety Committee for the animal studies, is overly stringent and should be reduced to 
BLl containment. The key issue with regard to clinical application is the level of AAT 
production. Normal individuals express very high endogenous levels of AAT and AAT 
deficient individuals express low levels of AAT; therefore, expression of the AAT 
transgene may not be distinguishable fi'om endogenous levels. While the investigators 
can conduct in situ vector RNA analysis, pathology studies, etc., quantitative data about 
vector-encoded AAT expression may be elusive. Dr. Miller suggested that the nasal 
mucosa experiment should be performed in large animals rather than in humans. 
Review-Dr. Zallen 
Dr. Zallen raised several concerns about the experimental design of this study in terms 
of risks and benefits, the informed consent process, and Informed Consent document. In 
her written review. Dr. Zallen questioned why tissues will be examined 72 hours after 
vector administration in the proposed human study, but the preclinical animal studies 
were conducted at 24 hours. Why were the animal experiments not extended to 72 hours 
to obtain comparable data? In their written response, the investigators stated that the 
protocol would be modified for the human experiment to include tissue examination 
between 24 and 48 hours following vector administration. How many patients will be 
entered onto the study? In their written response, the investigators stated that 5 patients 
will be entered on the bronchial instillation protocol and 6 patients will be entered on 
the nasal instillation protocol. Dr. Zallen expressed concern about possible conflict of 
interest as a result of investigators obtaining informed consent from their own patients. 
Under such circumstances, patients could feel obligated to participate in this study. A 
third party should be involved in the informed consent process. The investigators should 
elaborate on their comments regarding the lack of necessity for long-term follow-up. She 
noted Ms. Meyers' written comments about the failure to include information about 
alternative enzyme replacement (prolastin therapy) in the Informed Consent document. 
Other Comments 
Ms. Grossman agreed with Drs. Parkman and Millers' recommendations about the 
necessity for additional preclinical data derived from an appropriate animal model. Dr. 
DeLeon asked how expression of the transgene will be distinguished from endogenous 
AAT expression. Dr. Parkman explained that the investigators will conduct in situ RNA 
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Recombinant DNA Research, Volume 19 
