CONTACT: BECKY SOGLIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: Dec. 1, 1999
UI researchers: step made in developing gene therapy
to treat cystic fibrosis
IOWA CITY, Iowa -- A team of University of Iowa Health
Care investigators has advanced understanding of how gene therapy might effectively
treat the serious lung function loss associated with cystic fibrosis (CF).
Some basic problems have thwarted one gene therapy treatment approach which
involves using a vector -- a disabled virus or other carrier -- to insert
working copies of a specific mutated gene into an affected person's lung cells.
"The UI study addressed two fundamental problems currently
preventing progress of gene therapy for cystic fibrosis -- inefficient gene
transfer and lack of gene persistence," said Paul McCray, M.D., UI associate
professor of pediatrics and co-principal investigator. The team used human
cell cultures and in vivo, or animal, models to demonstrate both efficient
and lasting gene transfer into airway cells.
The investigators demonstrated functional gene activity
that lasted six months in the human cells in culture and six weeks in the
rabbits' airways. The findings were published online Nov. 24 by the Journal
of Clinical Investigation (available at: http://www.jci.org/cgi/content/full/199908390
). The print version will be published Dec. 6.
"This is another incremental step toward figuring
out how we might apply gene therapy to treat cystic fibrosis," McCray said.
"Our findings could lead to new approaches for future CF gene therapy trials."
People with CF have serious lung and digestive problems
due to malfunctioning ion channels that normally regulate salt and water secretions
to protect the lungs. A specialized protein called the CF transmembrane conductance
regulator (CFTR) makes the channel. However, in people with CF, the gene that
codes for the CFTR protein is mutated.
Previous research, including a 1998 study McCray led
using human cell cultures, demonstrated that a vector, which carries a working
copy of the mutated gene, can more effectively enter a cell if it is mixed
with a calcium chelator. The chelator binds with calcium to disrupt tight
junctions between the cells. The vector can then reach cell receptors and
transduce the cell -- cross its surface and deposit the gene.
In the most recent study, McCray's team used a new
vector from the retrovirus family, feline immunodeficiency virus (FIV), which
causes leukemia in cats but causes no disease in humans. Chiron Technologies
in San Diego created the FIV-based retrovirus.
"We saw in both human cell cultures and in rabbits
that FIV vectors will transduce, or infect, nondividing cells, which eliminates
the need to stimulate cell division to get the vector to work," McCray said.
"This is very important because normally very few lung cells are dividing."
McCray said the method of using a calcium chelator-enhanced
vector to bolster a vector's ability to transduce cells could be used in a
human trial to increase gene transfer efficiency.
"The principle applies to three classes of vectors
that investigators use to study gene transfer for cystic fibrosis -- retrovirus,
adenovirus and adeno-associated viruses," he said.
The UI study was also significant in its findings
on gene persistence, McCray added. The researchers found that the gene transferred
by the FIV vector into human airway cells in culture continued to show functional
CFTR activity for up to six months. In contrast, the effectiveness of an adenovirus
vector wore off after about three weeks. FIV-transduced gene expression in
the airway cells of live rabbits lasted six weeks (the duration of the study).
"We think the CFTR gene persists because the FIV vector
allows it into the chromosomes of lung cells with the potential to divide
and pass the gene on to their daughter cells," McCray said. "Unlike nonviral
carriers or an adenovirus, a retrovirus such as FIV has this ability."
In addition to McCray, UI investigators included Beverly
Davidson, Ph.D., associate professor of internal medicine and director of
the Gene Transfer Vector Core; Guoshun Wang, Ph.D., research scientist in
pediatrics; and Joseph Zabner, M.D., assistant professor of internal medicine.
The UI study was funded by grants from the Cystic
Fibrosis Foundation, the National Institutes of Health, and the Children's
Miracle Network telethon. McCray also received a Career Investigator Award
from the American Lung Association. Davidson and Zabner are Fellows of the
Roy J. Carver Charitable Trust.
Cystic fibrosis is the most common fatal hereditary
disease in the United States. According to the Cystic Fibrosis Foundation,
CF affects approximately 30,000 children and adults in the United States.
The disease occurs in approximately one of every 3,300 live births and is
usually diagnosed in early childhood. Lung function loss due to chronic infection
is the most common cause of the shortened life expectancy of people with CF.
University of Iowa Health Care
describes the partnership between the UI College of Medicine and the UI Hospitals
and Clinics and the patient care, medical education and research programs
and services they provide.