Recombinant DNA Advisory Committee - 12/2-3/93 
The study will utilize 3 ascending dosages of CFTR cDNA. Each patient will receive 
CFTR/liposome administration to one nostril and a mock transfection (lipid with DNA 
lacking CFTR) of the contralateral nostril as a control. The proposed DNA delivery 
system differs from the other CF protocols previously reviewed by the RAC. As noted 
previously by Dr. Crystal, there may be limitations to using the adenovirus vector; 
therefore, it is reasonable to investigate more than one gene delivery approach. Another 
cationic liposome CFTR protocol has been already initiated in the United Kingdom. In 
his initial review, Dr. Post requested the investigators to provide safety or efficacy data 
using the proposed cationic liposome, DMRIE/DOPE. The majority of the preclinical 
data was obtained using another lipid, DOTMA/DOPE, N-[l-(2,3-dioleoyloxypropyl)]-3- 
trimethylammonium-propane) / dioleoylphosphatidylethanolamine. Although the 
investigators might argue that the RAC has previously approved the DMRIE/DOPE 
system for Drs. Nabel and Rubin's studies, intranasal gene delivery to healthy CF 
patients raises safety issues different from those posed by intratumoral injection of 
terminally ill melanoma patients. The investigators have submitted additional data to 
demonstrate safety of the liposome and expression of a reporter gene in a rat model. 
These data are still too preliminary to justify approval of the human study. The 
investigators have outlined several ongoing safety experiments in the rat model involving 
short-term and long-term toxicity of the DMRIE/DOPE/CFTR construct. The strategy 
and preliminary data appear reasonable. Therefore, he recommended RAC approval of 
the protocol contingent on submission of data from these ongoing animal experiments. 
Dr. Post asked the investigators to respond to several other questions. Where does the 1 
ml volume of the DNA/liposome mixture go after intranasal administration? Would a 
device designed to prevent nasal drainage be useful? Does the DNA integrate into 
chromosomes? What is the expected duration of gene expression using this method of 
delivery? In response to a previous suggestion by Dr. Miller, the investigators have 
deleted an open reading frame encoding 44 amino acids from the carboxy terminus of 
the SV40 small T antigen of the pKCTR vector. Has this modification been 
incorporated into the control vector? 
Dr. Walters asked whether the liposome delivery method poses less of a public health 
concern than adenovirus vector delivery? Dr. Post answered that liposome delivery 
presents a lesser degree of risk. 
Review--Dr. Krogstad 
Dr. Krogstad asked about the investigators' degree of confidence, from an anatomic and 
functional point of view, that the liposome material will remain in the nostril. Could 
fluorescein be used diagnostically to answer this question? What is the level of 
sensitivity of the bioelectric potentiometric assay for the detection of CFTR expression? 
Is this assay sensitive enough to detect differences between the treated and untreated 
nostrils? Based on Dr. Crystal's results, detection of CFTR expression is not a trivial 
problem. What are the possible risks associated with liposome delivery of CFTR to the 
nasal epithelium? Can the knowledge gained from this trial be successfully translated 
into a therapeutic treatment for CF? From a mechanical point of view, what is the 
Recombinant DNA Research, Volume 18 
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