Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 288

6.4 Applications of Gene Therapy in Cystic Fibrosis
Cystic fibrosis (CF) is one of the most common chronic progressive and frequently
fatal autosomal recessive genetic diseases affecting the body's exocrine glands. CF
is caused by mutations in the cystic fibrosis transmembrane conductance regulator
( CFTR ) gene, located on the long arm of chromosome 7 [152,153] . The normal CFTR
gene encodes for formation of chloride channel protein, responsible for salt balance
across the cell membrane [154,155] .
In CF patients, CFTR is unable to perform the normal functions, leading to dehy-
dration of affected organs such as the sweat glands, lungs, pancreas, and digestive
system. Because lungs are the primary organs affected in CF patients, pulmonary
symptoms are responsible for the majority of mortalities [156,157] . The hallmarks
of CF lung disease are early, severe, and sustained neutrophil-mediated inflamma-
tion and persistent infection with a relatively narrow range of bacteria [158] . Gene
therapy provides a treatment strategy for CF patients because it targets the cause of
CF rather than just treating the symptoms. There are several factors that account for
the high level of interest in a gene therapy approach to CF, such as the following:
l The genetics of CF are straightforward, and it is the most common lethal inherited disease
in Caucasian populations.
l The lung is predominantly responsible for the morbidity and mortality in CF patients. It is
easily accessible by noninvasive methods like inhalation of aerosols.
l Current treatment is aimed at slowing the inevitable progression of lung disease, rather
than halting it or even preventing its onset, and many gene therapy trials expressing less
than 100% gene transfer modulate CF.
Gene therapy of CF involves the insertion of a normal copy of the CFTR gene into
affected cells, which could potentially correct the biochemical abnormality of these
cells and thus prevent or ameliorate disease in that organ. Because the pulmonary
consequences of the disease are largely responsible for the morbidity and mortality
of CF, the respiratory tract is the obvious target for the majority of these studies for
CF gene therapy, rather than other organs [159] .
6.4.1 In Vitro CFTR Transfer Studies
Many in vitro studies have been conducted to deliver the CFTR gene. In the first report,
CFTR cDNA was transferred using retrovirus, normal CFTR mRNA in pancreatic car-
cinoma cell line was detected [160] . Later, the CFTR cDNA gene was delivered using
vaccinia virus [161] , adenovirus [162,163] , which resulted in the correction of CFTR
defects in vitro . Furthermore, many nonviral carriers have also been tried for CFTR
delivery under in vitro conditions [164] .
6.4.2 In Vivo CFTR Studies
The encouraging results of in vitro delivery of CFTR gene studies led to in vivo CFTR
gene delivery in animal models, using viral and nonviral vectors. The Ad virus-mediated