News & Updates
Research Advances:
From Molecular Genetics Questions to New Therapies for Cystic Fibrosis
One of the major challenges in treating
patients with cystic fibrosis (CF) is clearing
the abnormally thick and sticky mucus from
the airways, in order to prevent obstructive lung
disease and chronic bacterial infections that may
lead to lung failure–a major cause of mortality
in CF patients. At Children's Memorial Research
Center, molecular geneticists are approaching this
challenge by trying to clarify the mechanisms that
alter the biochemical and biophysical properties
of mucins (or mucus proteins) in CF. This is a very
promising direction for CF research, with a strong
potential to translate into new targeted therapies,
according to Ann Harris, PhD, who heads
the Human Molecular Genetics Program at the
research center and is a professor of pediatrics at
Northwestern University's Feinberg School of Medicine.
She also is the Valerie and George D. Kennedy
Research Professor in Human Molecular Genetics.
How are Mucins Changed in CF?
Research led by Harris determined that contrary
to expectations, the sugar structures of mucins are
not affected directly by the basic genetic defect
responsible for the disease–mutations in the cystic
fibrosis transmembrane conductance regulator
(CFTR) protein. "Most likely, the problem occurs
once mucins are released outside the cell," she
explains. "Something in the external milieu that
is affected by the CFTR defect may be changing
mucin properties, which may signal the cell to
make more mucins or cause them to be released
differently." Mucins play a central role in protecting
the cell from fluctuations in the external environment,
such as dehydration or bacterial infection.
They also are involved in transmitting messages
across the cell membrane, helping to regulate the
cell's response to external stimuli. Harris' team is
testing the hypothesis that certain proteases in
the CF lung environment cleave mucins at a higher
rate, and while one part is released from the cell
membrane, the remaining part sends messages
back to the cell that new mucin molecules need
to be synthesized. "We are trying to identify the
proteases that may be causing the release of
mucins, so that targeted protease inhibitors can
be developed to normalize the process in cysticfibrosis. This could alleviate the
disease and be extremely helpful
to patients."
Finding CFTR Gene Switches
The Harris laboratory is pursuing
another path that may
enable the next generation
of gene therapy to reduce or
prevent lung infection in CF
patients. "We want to find
the switches that normally
turn the CFTR gene on and
off in various cell types," says
Harris. "With this knowledge,
the corrected gene can be
delivered to any cell type, but
only switched on in cells that
normally express CFTR, increasing
effectiveness of gene therapy. Lack of tissue
specificity was one of the many technical problems
with the earlier unsuccessful attempts to use viral
vectors as a gene therapy delivery method."
One of the puzzles presented by the CFTR gene is
that its promoter, or the region that signals a gene
to turn on and off, does not have elements that
control CFTR expression in different cell types of
the body. So far, Harris' team has identified candidate
regulatory elements in other sections of the
CFTR gene. "We are looking at the whole genome
of a living cell, trying to discover how the different
pieces of DNA, the different CFTR regulators work
together," explains Harris.
Keeping Research Relevant
A close interaction with the Cystic Fibrosis Center
of Children's Memorial Hospital helps the researchers
in Harris' laboratory ask relevant questions.
"Our work must be focused on finding solutions to
the current struggles faced by patients. We rely on
the ongoing clinical perspective to make sure that
the basic research we pursue is geared toward
better treatments," emphasizes Harris.
Reprinted with modifications from The Child's Doctor,
Fall 2006, by Vita Lerman
