DiagnosticsCould Science Use The Common Cold To Cure Cystic Fibrosis?
In 1989 scientists identified the gene mutation that causes cystic
fibrosis (CF), which led to the hope that CF lung disease could be "cured"
using gene therapy. The premise of gene therapy is that modified viruses
or other gene-based systems could be used to deliver a corrected version
of a
gene into affected tissues. However, the projected cure has been hampered
by the natural ability of the lung to limit the introduction of foreign
genes into its cells. Now, University of North Carolina at Chapel Hill
School of Medicine scientists have found what may be the most efficient
way to
deliver a corrected gene to lung cells derived from CF patients, renewing
hope that gene therapy for CF lung disease could be a successful future
treatment.
While Cystic Fibrosis is a multiple organ disease, it most devastatingly
affects the lung. In people with CF the airways are clogged with mucus
that
is dehydrated and thicker than normal. The inability to clear mucus from
the lung increases the susceptibility of CF patients to lung infections,
which results in lung damage. Over the last two decades scientists have
developed a variety of viral and non-viral vector systems suitable for
delivering a corrected CF gene back into lung cells grown in the
laboratory. Several of these vectors systems have been tested in human
clinical
trials. However, the efficiency of gene delivery achieved in the
laboratory has not borne out in the clinical studies, suggesting that the
cell models
used in the laboratory do not represent the status of the cells in
patients" lungs. Scientists have since developed laboratory models of
human lung
cells derived from CF patients that recapitulate the architecture and
function of the cells present in the human lung. Studies using such cell
models
have revealed that previously used vector systems cannot deliver the
corrected CF gene to enough lung cells to be of clinical benefit to CF
patients.
In this new study reported today in PLoS Biology, UNC scientists took a
different approach and used parainfluenza virus, a virus known to infect
human
lung cells and to cause common colds. The UNC scientists engineered this
virus to contain the corrected CF gene and found that it could deliver
this
gene to 60-70% of lung cells although only 25% of cells needed to be
targeted to restore normal function back to the tissue model. "This is the
first demonstration in which we"ve been able to execute delivery in an
efficient manner to a tissue that resembles what is present in the lung,"
said Ray Pickles, Ph.D., associate professor of Microbiology and
Immunology at the Cystic Fibrosis Research and Treatment Center and the
Department of
Microbiology and Immunology. "When you consider that in past gene therapy
clinical trials, the targeting efficiency has been somewhere around 0.1
percent of cells at best, you can see this is a giant leap forward."
"We discovered that if you take a virus that has evolved to infect the
human airways, and you engineer a normal CF gene into it, you can use this
virus to correct hallmark CF features in the model system that we used,"
he said. For instance, the experiment restored the cells" ability to
hydrate and transport mucus secretions making the CF cells function
essentially like normal cells.
Now the researchers must work to ensure the safety of the delivery system.
In a pleasant surprise, simply adding the CF gene to the virus
significantly attenuated it, potentially reducing its ability to cause an
inflammatory reaction. But the scientists may need to alter the virus
further. "We haven"t generated a vector that we can go out and give to
patients right now," Pickles said, "but we are slowly but surely moving
forward towards this goal" Pickles says. "It is going to require a long
term commitment from the CF gene therapy field that has achieved so much
this far and it"s only a matter of time until we understand how to do this
reproducibly and safely".
Funding:
This work was funded by the National Institutes of Health (NIH)
and Cystic Fibrosis Foundation (CFF) grants NIH R01 HL77844 (RP), NIH P01
HL051818 (RP); NIH Molecular Therapy Core Center P30 DK065988 (RB, SG,
RP); CFF ZHAN03I0 (LZ), GABRIE04G1 (SG) and GABRIE05P0 (SG); and the NIAID
Intramural Research Program (MS, LV, PC). The funders had no role in study
design, data collection and analysis, decision to publish, or preparation
of the manuscript.
Competing interests statement:
The authors declare that no competing interests exist.
Citation:
"CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium."
Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, et al. (2009)
PLoS Biol 7(7): e1000155.doi:10.1371/journal.pbio.1000155
PLoS Biology