Abstract and Introduction
Abstract
Cystic fibrosis (CF) is a single-gene disorder with insufficient treatment options and a target organ, the lung that is relatively easily accessible. Thus, it is not surprising that in the early years of gene therapy, CF was at the forefront of this field. Since cloning of the CF gene in 1989, 25 Phase I/II clinical trials involving approximately 420 CF patients have been carried out using a variety of viral and nonviral gene transfer agents. Most early trials focused on the nasal epithelium as a surrogate for the lung to allow for easy access and sampling, and, importantly, to ensure safety. Once an acceptable safety profile had been established, gene transfer agents were administered directly into the lung. Although many of these trials established proof-of-principle for gene transfer in the airways, a gene therapy-based treatment has not yet been developed. Here, we will summarize the key findings of these clinical studies and describe current preclinical and clinical research aimed at further developing gene therapy for CF.
Introduction
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the Caucasian population, and affects approximately 70,000 individuals worldwide. Although several organs are affected, severe lung disease is the cause of most of the morbidity and mortality in individuals with CF. The CF gene, the cystic fibrosis transmembrane conductance regulator (CFTR), was cloned in 1989, and codes for a chloride channel located in the apical membrane of epithelial cells. Mutations in the CFTR gene lead to imbalanced ion and water movement across the airway epithelium, resulting in an accumulation of sticky mucus, chronic bacterial infection and inflammation. CF is a single-gene disorder with insufficient treatment options and comparatively easy access to the target organ, the lung, and was, therefore, one of the first diseases to be considered for gene therapy. Following cloning of the gene, proof-of-principle for CFTR gene transfer was quickly established in vitro and in animal models. However, despite the theoretical ease of noninvasive access to the lung, gene transfer into the airway epithelium of man has been comparatively inefficient, and it is unclear if the current level of gene transfer efficiency is sufficient to ameliorate CF lung disease (see later).
The lung is a complex organ and can be roughly divided into two main regions: the airways, consisting of trachea, bronchi and bronchioles that transport air to the peripheral lung, and the alveoli, where gaseous exchange takes place. Although various pulmonary cells express CFTR (albeit at low levels), the ciliated epithelial cells in the airways are, in our view, currently the best target for CF gene therapy. The lung and, importantly, ciliated epithelial cells have evolved to fight invasion of foreign particles, and gene transfer agents (GTAs) have to overcome a number of extra- and intracellular barriers to achieve their objective. Over the past decade, the gene therapy community has recognized that there is no one vector that is effective for all applications, but that the GTA has to be chosen carefully depending on the cell type to be targeted, the number of treatments (one vs repeat administration) required, and the size and nature (secreted vs cellular product) of the gene to be delivered. Since cloning of the CF gene in 1989, 25 Phase I/II clinical trials involving approximately 420 CF patients have been carried out using a variety of viral and nonviral GTAs Here, we will review the current state of CF gene therapy and highlight the successes and failures that have contributed to our current knowledge pertaining to the potential of gene therapy for treating CF.