CONTACT: BECKY SOGLIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-9917
UI researchers find potential gene therapy for cystic fibrosis
IOWA CITY, Iowa --A team of University of Iowa investigators may have
found a way to permanently deliver therapeutic genes to the lungs of patients
with cystic fibrosis (CF), the most common fatal hereditary disease in
the United States.
The research using human cells in laboratory cultures indicates that
the method could be used to permanently cure CF and other genetic lung
diseases, said Dr. Paul McCray, associate professor of pediatrics in the
UI College of Medicine and co-principal investigator.
The findings were published in the December issue of the Journal of
Virology. The other co-principal investigators of the study were Beverly
L. Davidson, Ph.D., UI associate professor of internal medicine and director
of the Gene Transfer Vector Core, and Guoshun Wang, Ph.D., UI research
investigator in pediatrics.
According to the Cystic Fibrosis Foundation, CF affects approximately
30,000 children and young adults in North America. The disease occurs in
approximately one of every 3,300 live births and is usually diagnosed in
early childhood. Reduced lung function, lung infection and liver and pancreatic
disease are among the serious conditions that can reduce the life expectancy
of a person with CF. The median age of survival for a person with the disease
is 31 years.
CF is caused by the malfunction of an ion channel that regulates secretion
of salt and water that protect the lungs. A specialized protein, known
as the CF transmembrane conductance regulator (CFTR), makes the channel.
The gene that codes for the CFTR protein is mutated in people with CF.
McCray said the UI research project was designed to complement other
CF treatments under laboratory investigation, including another UI study.
Those methods involve inserting the CFTR gene into a vector-a nonviral
carrier or an adenovirus-to facilitate transferring the gene into cells
lining the airway.
In some cases, the mucous produced by the diseased lungs may trap the
vector and prevent it from depositing the CFTR gene in the cells. With
chemical assistance, the vector successfully inserts the gene into the
cells and CFTR is produced. While the results are beneficial, the effect
is not lasting because the gene itself is not reproduced as the cells divide.
Because CF is a chronic, progressive disease, the CFTR gene would have
to be reintroduced to maintain production of the protein that protects
the ion channel.
In the study led by McCray and researchers at the UI and Chiron Laboratories
in San Diego, the team found that a retrovirus "might be used on a
one-time basis and offer a permanent cure for patients with cystic fibrosis,"
A retrovirus, unlike a nonviral carrier or an adenovirus, can integrate
into the host DNA.
"A retrovirus has the advantage of permanently placing its gene
into the host cell," McCray said. "So when the cells divide,
they are able to reproduce the gene."
In the case of CF, the gene would then code for the needed protein,
CFTR, on an ongoing basis, allowing the ion channel to function properly.
At the same time, the team found that there are limitations that prevent
the easy introduction of the retrovirus, known as murine leukemia virus
(MuLV), into the airway cells. The investigators discovered that the retrovirus
cannot easily cross the apical, or top, surface of the cells.
Searching for a way to overcome that difficulty, the team found that
the retrovirus readily enters cells from the basolateral, or bottom, side
of the cells. The study results suggest that the bottom surface of the
cells has receptors that accept the retrovirus.
In addition, the team studied whether disrupting the tight junctions
between the cells would make it easier for the retrovirus applied to the
apical surface to enter and deliver the CTRF gene. The junctions require
calcium, which can be removed through treatment with EGTA, a chemical that
binds with calcium.
"Removing the calcium from around the cells opens the tight junctions,
which act as a sort of cement between the cells," McCray said. "When
the junctions open, the retrovirus can reach the receptors."
The researchers will continue their studies of the MuLV-based retrovirus
gene transfer. "Our next step is to develop methods to apply this
approach to an animal model," McCray said. "Our early experiments
In a previous cystic fibrosis-related study at the UI, a team of investigators,
including Dr. Michael Welsh, professor of internal medicine and Howard
Hughes Medical Institute investigator, studied the use of an adenovirus
in ferrying the CFTR gene into airway cells.
Welsh and his colleagues found that an adenovirus coupled with a calcium
phosphate complex can more easily enter human airway epithelial cells in
culture than when the virus alone is used. The team found that the gene
is then transferred to a sufficient number of cells to ultimately correct
the ion channel deficit. The findings of that study were published in July
in the Journal of Clinical Investigation.