Protocol 
Gene Therapy for CF using Cationic Liposome Mediated Gene Transfer : Phase I Trial 
PROTOCOL 
LA. PURPOSE OF THE PROJECT 
Cystic fibrosis (CF) is a common, lethal, inherited disease among Caucasian children and 
young adults. While the pathophysiology of CF includes many organ systems (e.g., gastrointesti- 
nal, reproductive, endocrine) the predominant cause of death is respiratory failure (1). 
Hyperviscous respiratory secretions and related chronic pulmonary infections lead to scarring 
and fibrosis of the lungs, deteriorating pulmonary function, and death, with an average CF life 
expectancy of approximately 29 years. The disease is caused by mutations in the cystic fibrosis 
transmembrane conductance regulator (CFTR) gene (2-4). The CFTR functions, at least in part, 
as an epithelial chloride channel which resides in the apical membranes of exocrine gland 
epithelial cells (5-10). It has been suggested that the fluid and electrolyte content of normal 
respiratory mucous is dependent upon CFTR chloride channel activity, and that failure to secrete 
chloride by CF cells results in diminished hydration of mucous, sputum hyperviscosity and the 
pulmonary sequelae of the disease. 
Transfer of normal human CFTR to cells possessing the CF ion transport phenotype (i.e. , 
with defects in Cl' transport), or into the respiratory epithelium of CF mice leads to re- 
establishment of CFTR mediated chloride transport (9-11). Findings of gene transfer mediated 
correction of the CF bioelectric defect in these model systems, together with the failure of 
current therapies to allow CF patients to live beyond young adulthood, indicates the need for 
new approaches to CF therapy and the possibility of gene transfer-based protocols in the disease. 
Five gene transfer based protocols using recombinant adenovirus to deliver functional CFTR to 
limited regions of CF respiratory epithelium have been approved previously for use in humans 
by the Recombinant DNA Advisory Committee of the N.I.H. (12). Evaluation of the safety and 
efficacy of adenovirus-based CFTR delivery is currently in progress. 
The present protocol is intended to evaluate an alternative, cationic liposome-based 
mechanism of delivery of normal CFTR to nasal respiratory epithelia of CF patients. The 
advantages of lipid-based gene transfer are evident, and may include 1) minimal toxicity, 2) less 
antigenicity than viral DNA delivery vectors, and 3) efficient gene transfer even to non- 
replicating cells (11, 13-15). The nasal airway epithelium is an ideal model for gene transfer of 
this type, since this epithelium exhibits a CF bioelectric defect and is easily accessable for 
studies of both safety and efficacy of DNA/vector administration (12, 16-18). In addition, the 
use of this site in CF patients greatly minimizes the risk of serious complications related to gene 
transfer to the lower airways. 
LB. BACKGROUND 
I.B.l. Clinical Aspects and Standard Care. 
Cystic Fibrosis is an autosomal recessive disease with a prevalence of approximately 
1:1600 live births among Caucasian individuals of European descent (1). While the modem 
hallmark of the disease is respiratory failure, the disease often presents as growth retardation in 
infants or young children. Poor growth in most cases is attributable to exocrine pancreatic 
insufficiency and chronic dietary malabsorption. Histopathologic examination of CF pancreatic 
specimens demonstrates extensive destruction including dense fibrosis with formation of large 
cystic structures (hence the full name of the disease, "cystic fibrosis of the pancreas"). The 
pathologic changes in the pancreas have been ascribed to primary abnormalities in content and/or 
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Recombinant DNA Research, Volume 18 
