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GENE
THERAPY OFFERS HOPE FOR A BETTER LIFE
Med Center at Work on Research
BY THERESA CHA -- Lincoln Journal Star
Pain has plagued Kevin Nevrivy for as long as he can remember.
Constant, excruciating pain in his muscles and joints. Pain that intensifies
with fluctuations in the weather and humidity. Pain that causes deep depression.
"It's something you don't want to have, I guess," said the soft-spoken Ord
man. "This is a most dreadful, excruciating, disabling disease that I wouldn't
wish on a dog." Starting as a child, he saw doctors across Nebraska - 15
doctors, including two specialists, in Ord, Broken Bow, Kearney, Grand Island
and Lincoln - who thought he had everything from appendicitis to growing
pains to osteo-arthritis. Finally, in May, an Omaha geneticist diagnosed
the 29-year-old with a rare genetic disorder called Fabry's Disease. "I
was finally glad to hear I had something," said Nevrivy, who dreams of being
well enough to farm some day. For now, he said, his only relief is to lie
in his semi-dark, climate-controlled bedroom, quietly watching TV, listening
to the radio, reading or sleeping.
"Quite a life. You can have it cheap or for free."
Estimated to affect anywhere from a few thousand to 50,000
people worldwide, Fabry's is a metabolic disorder that prevents the body
from making an enzyme that gets rid of fatty chemicals, said Dr. G. Bradley
Schaefer, who diagnosed Nevrivy. The resulting chemical build-up can cause
heart, kidney and nerve problems. Disease symptoms include severe pain,
fatigue and trouble regulating body temperature.
Kevin's father, Joe Nevrivy Jr., remembers the first
time he noticed something wrong with his son.
"He was about 2 years old and his feet turned hotter than
bricks," said the Ord farmer. "My wife used to put wet wash cloths on him."
Three members of the
Nevrivy family of rural Ord live life governed by the effects of
a rare genetic disorder called Fabry's Disease. Those afflicted
are (from left) Frank Patrick, 34, Kevin Nevrivy, 29, and Bryon
Nevrivy, 28. They are shown here with their sister Jogie, her son,
David, and their dad, Joe Nevrivy Jr. (courtesy photo) |
But that didn't seem to help much.
There were days when Kevin was so uncomfortable he couldn't walk or tolerate
socks on his swollen feet.
Three of six children in the family
have the disease - Kevin, his half-brother, Frank Patrick, 34, and his
brother, Bryon Nevrivy, 28.
"Frank and Bryon started having symptoms
around age 10," the father said. "But Kevin, he's the worst one."
The pain cuts through medication, his symptoms worsening
on hot or humid days. He's never been able to play sports with his friends.
He wasn't able to attend school past the 10th grade. And he has been unable
to work most of his life.
"All I know is when I wake up, it's there," Kevin Nevrivy
said. "And it gets worse as the day goes along."
Help may be around the corner. Thanks to gene therapy
research, treatment in the form of enzyme replacement is within months
of being on the market, Schaefer said. If it works, the treatment could
relieve many of the disease symptoms and stop its progression.
Gene therapy, as defined by the American Society of
Gene Therapy, is the treatment of disease by either replacing damaged
or abnormal genes with normal ones or providing new genetic instructions
to help fight disease.
As an extension of conventional medicine, the goal of
gene therapy is to treat disease by administering genetic material rather
than a drug. Theoretically, a disease may be cured by a single administration
of gene therapy.
Reality tells a different story.
"The original intent of gene therapy was to treat patients
who had genetic abnormalities," said Dr. Ira Fox, associate dean for research
and development at the medical college of the University of Nebraska Medical
Center in Omaha.
"Well, it turned out that's a lot
harder than anyone ever thought it was going to be."
For more than 10 years, scientists have been working
to find gene therapies for such conditions as cancer, arthritis, vascular
disease and genetic disorders. As yet, no one has discovered a bankable
method. But that hasn't deterred them.
From 1989 to May 2000, the U.S. Food and Drug Administration,
which oversees all clinical research, received more than 280 new gene
therapy study proposals;55 were submitted in fiscal year 1999 alone.
The University of Nebraska Medical Center in Omaha has
not done clinical gene therapy trials, but scientists there are engaged
in some basic research.
Dr. James Talmadge (right), here in his
lab at the University of Nebraska Medical Center, focuses on developing
clinical cancer therapies. He is studying how gene therapy can be
used to kill breast cancer cells. (photo by TED KIRK/Lincoln Journal
Star) |
"It's not Penn, it's not Michigan, it's not UCSD,
but we do some here," said James Talmadge, UNMC professor of pathology
and microbiology.
"Our program is only emerging here and cannot be compared
to these institutions, but we do some world-class research and strongly
believe in the future of our gene therapy program," said Talmadge's colleague,
Professor Alexander Kabanov. Successful gene therapy depends on two factors:
delivering genetic material to the right cells and ensuring the gene works
once it gets there. Finding an effective and safe vector - the vehicle
that delivers therapeutic genes - is the key to solving the first problem.
Four professors at UNMC are working in concert to do
just that. As part of the Nebraska Research Initiative, Talmadge, Pi-Wan
Cheng, Vinod Labhasetwar and Alexander Kabanov have been working together
for the past three years. Each brings a unique perspective to the effort.
Talmadge focuses on developing clinical cancer therapies.
He is studying how gene therapy can be used to kill breast cancer cells,
collaborating with Dr. Roy Baynes at the Karmanos Cancer Institute in
Detroit. They recently got FDA approval for a phase I clinical study.
They will test the efficacy of an adenovirus vector carrying p53, a tumor-suppressor
gene, to kill tumor cells found in breast cancer stem cell transplants
following high-dose chemotherapy. But first, a little background.
Vectors come in two main categories: viral and nonviral.
Viruses are the smallest, simplest life forms. They cannot reproduce unless
they enter a living cell. They have a natural delivery system that allows
their DNA to enter a host's genome, be it plants, bacteria, animals or
humans. Disease-causing viruses have an enormous effect on the world,
causing, for example, influenza, small pox, AIDS, the common cold and
some forms of cancer. 
The same characteristic that makes them so efficient
at spreading disease can be used for good in the form of vectors. A virus'
disease-causing genetic material can be removed and replaced with therapeutic
genetic material.
In Talmadge's study, the adenovirus, which causes upper
respiratory and eye infections in humans, has been modified to carry a
tumor-suppressing gene. Previous laboratory studies have shown tumor growth
inhibition in cells infected with the p53-carrying vector. Talmadge hopes
to use this technology in cancer treatments.
But viral vectors can cause such harmful side effects
as an inflammatory immune response, and they cannot be targeted to every
cell type. Viral vectors only infect cells for which they have a natural
affinity.
That's where nonviral vectors offer an advantage. As
tiny, man-made structures that carry and release therapeutic DNA into
cells, they can be designed to diminish adverse immune response. They
can also be targeted to a variety of cells. Latecomers onto the gene therapy
scene, nonviral vectors are used inabout 12 percent of gene therapy clinical
trials in the United States and Europe, Kabanov said.
But nonviral vectors come with a major disadvantage:
They are generally less effective than viral vectors in delivering therapeutic
DNA - some up to a million times so.
Cheng, Kabanov and Labhasetwar study nonviral vectors.
Cheng is studying the effectiveness of a vector composed
of a cationic liposome and a cell-targeting molecule. He has used this
vector to successfully deliver the p53 gene to suppress growth of prostate
cancer cells in mice. He is also investigating the system in treating
cystic fibrosis.
Labhasetwar |
Labhasetwar is investigating the effectiveness of biodegradable nanoparticles
in gene delivery to treat cancer and various metabolic diseases. Nanoparticles
are minute "beads" measuring about 100 nanometers in diameter, he explained.
A nanometer is one billionth of a meter. The diameter of a typical virus
is 100 nanometers.
Therapeutic DNA is put into these beads and released
once it enters the target cell. Labhasetwar also is studying the possibility
of using this system in pill, instead of injectable, form for enzyme replacement
therapy for metabolic disorders.
Kabanov also uses nanotechnology to design artificial
vectors.
The principle difference between the systems Kabanov
and Labhasetwar are studying: Kabanov is making polymers - molecules that
make up common, plastic objects - "smart" enough pass through different
environments in the body so it can release the therapeutic DNA once it
gets inside the target cell.
Labhasetwar aims to retain the curative DNA-containing
polymer in the body for a long time so it can be released gradually as
the polymer degrades, increasing therapeutic effect.
Kabanov, an award-winning scientist and a pioneer in
using polymers for gene delivery, believes finding an effective vector
is incredibly complex.
"It is one of the most challenging tasks I have encountered
in my life," he said. "We're trying to teach each other what we can do,
a multi-disciplinary approach, the main goal being effective gene therapy."
How far away they are from that goal depends on whom
you ask. Answers ranged
from five years to 50 years.
"When I talk about gene therapy, the first thing I
always emphasize is that people not develop false hopes ...," said Schaefer.
"I wouldn't count on gene therapy rescuing people in
the next 20 years or so. I think that's an impression that's really being
kind of oversold to the public. ... It's nowhere close to being practical,
clinical treatments at this point."
Schaefer sees more potential in the near future for
intermediary genetic therapy such as making replacement enzymes for metabolic
genetic disorders like Fabry's Disease. Using cloning techniques to grow
a burn victim's own skin instead of transplanting donor skin. Using gene
therapy to reduce plaque in heart tissue.
"That's where I think all the action's going to be
in the next 30 to 40 years," Schaefer said. "I think people need to understand
there are these intermediate types. ... That's where most of the action's
going to be rather than true cures at the gene level."
For Kevin Nevrivy and his family, even intermediary
treatment could be a godsend. The dawning promise of enzyme replacement
therapy has shifted his outlook on life.
"This is the way I've been since I remember," he said,
describing how the best he could do was live hour by hour. "I hope, I
guess, to live my life better than I have and look forward to a future.
I never looked forward to something like that before."
Reach Theresa Cha at 473-7228 or tcha@journalstar.com.
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