Gene Therapy for Cystic Fibrosis Using Cationic Liposome Mediated Gene Transfer: A Phase I Trial of Safety and Efficacy in the Nasal Airway. University of Alabama at Birmingham,Birmingham,Alabama

Scientific Abstract

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., gastrointestinal, reproductive, endocrine) the predominant cause of death is respiratory failure. 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. The CFTR functions, at least in part, as an epithelial chloride channel which resides in the apical membranes of exocrine gland epithelial cells. It has been suggested that the fluid and electrolyte content of normal respiratory mucus 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 reestablishment of CFTR mediated chloride transport. 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 in vivo have been approved previously for use in humans by the Recombinant DNA Advisory Committee of the N.I.H. 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 nonreplicating cells. 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. 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.

NON-TECHNICAL ABSTRACT

Cystic fibrosis (CF) is a common inherited disease, affecting about 1 in 1600 Caucasians. Most patients with cystic fibrosis die before age 30. The disease can affect many parts of the body (including the pancreas, reproductive glands, and sweat glands), but the cause of death is usually due to lung failure from thick secretions and chronic infection of the lungs.

Human genes carry functions which are necessary for healthy human life. Cystic fibrosis is caused when one of these genes, called the cystic fibrosis gene, cannot function properly. As a result of this dysfunction, tissues in the bodies of CF patients (and the cells which are the building blocks of these tissues) cannot move salts properly. For example, the high content of salt in the sweat of CF patients, and the thick respiratory mucus in the lungs of CF patients, have both been associated with difficulties moving salts such as sodium and chloride.

The purpose of this study is to determine whether normal, functional copies of the CF gene can be delivered to the cells lining the nose of CF patients. This study will use small amounts of molecules of fat (also called “lipids”) to carry the normal gene into these cells.

This study has two goals. The first goal is to determine whether lipids can be used to safely carry the normal gene into the cells lining the nose. The second goal is to determine whether after receiving the normal CF gene, the inside of the nose will develop an improved ability to move salts.

The use of genes to treat human diseases has been called “gene therapy.” Because the serious complications of CF occur in parts of the body other than the nose (for example, in the lungs and pancreas), it is unlikely that the delivery of a normal CF gene to the inside of the nose will make participants in this study healthier. On the other hand, the overall goal of this research study will be to allow the possibility of attempting the same type of normal gene delivery to CF lungs, with the hope of developing better treatments for cystic fibrosis.