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Growth-factor antibody may treat chronic
lung disease affecting premature infants
MGH-Genzyme collaboration identifies
potential therapy for condition affecting growth, development
BOSTON - April 2, 2007 - Researchers from Massachusetts General
Hospital, in collaboration with scientists from the Genzyme
Corporation, have identified a potential treatment for a chronic
lung disease affecting premature infants. In a study to appear in
the American Journal of Physiology - Lung Cellular and Molecular
Physiology, which has received early online release, the scientists
find that the activity of transforming growth factor-beta (TGF-beta,
a protein that controls many essential cellular functions) is elevated
in the lungs of an animal model of bronchopulmonary dysplasia and
that treatment with an antibody to TGF-beta both decreased the growth
factor's activity and improved lung development.
"Our findings show for the first time that TGF-beta is a major
player in causing bronchopulmonary dysplasia and that inhibiting
its activity in the injured newborn lung may decrease the severity
or incidence of this disease," says Jesse Roberts Jr., MD,
of the MGH departments of Anesthesia
and Pediatrics
and the Cardiovascular
Research Center, the paper's senior author. "Since bronchopulmonary
dysplasia is the most significant lung disease of premature infants,
these results are very exciting."
Bronchopulmonary dysplasia (BPD) affects about 15 percent of premature
infants, resulting in chronic lung disease in 10,000 to 20,000 infants
in the U.S. each year, and is often caused by the mechanical ventilation
and oxygen therapy required for their survival. Since BPD is more
common in the most premature infants - affecting nearly 65 percent
of those with a birth weight less than 1 pound, 10 ounces - its
incidence has increased as more of the tiniest infants are surviving.
The lung damage produced by BPD is usually chronic, requiring long-term
treatment and frequently affecting growth and neurological development.
BPD is second only to asthma as the most costly disease of children
in the U.S., and infants with BPD who survive can have lung disease
into adulthood.
Previous studies have shown that TGF-beta helps regulate early fetal
lung development, but its direct role in the maturation of pulmonary
structures disrupted by BPD has not been known. Since research at
other centers has suggested that elevated TGF-beta levels might
interfere with later lung development, the MGH-led team investigated
that possibility and its potential relationship to BPD. A group
of pregnant mice received injections of either an antibody against
TGF-beta or a control substance a few days before giving birth.
Their offspring were housed in either normal air or 85 percent oxygen,
a concentration known to cause BPD in mice, for 10 days after birth.
The newborn mice exposed to high oxygen levels without the neutralizing
antibody treatment were found to have elevated TGF-beta activity
in the peripheral regions of their lungs. Those mice also had incomplete
development of the lung structures called alveoli and the tiny pulmonary
blood vessels where gases are exchanged between the airway and the
bloodstream, a deficit typically seen in BPD. The mice that also
received the TGF-beta neutralizing antibody had significantly lower
levels of growth factor activity and much more normal lung development.
Moreover, the improved lung development of the mice exposed to high
levels of oxygen and treated with the neutralizing antibody was
also associated with improved body growth. Those mice grew at a
rate virtually identical to that of the animals that breathed normal
air. Mice not treated with the antibody and exposed to elevated
oxygen weighed 30 percent less than the air-breathing control group
did at 10 days old.
"These findings need to be confirmed in other models of this
disease, and the treatment's safety needs to be evaluated before
we can plan a clinical trial, but it's quite possible that this
therapy will help us treat these very sick babies," Roberts
says. "It also is not far-fetched that TGF-beta-neutralizing
therapies might have therapeutic potential in other human diseases.
Studies are underway right now at our center and several others
to evaluate that possibility." Roberts is an associate professor
of Anaesthesia (Pediatrics) at Harvard Medical School and a neonatologist
and pediatric anesthesiologist at the MassGeneral Hospital for Children.
The use of TGF-beta antibody to treat BPD was co-invented by Roberts
and study co-author James Streisand, MD, an MGH anesthesiologist
and clinical scientist at Genzyme Corporation; and the invention
has been patented by the MGH and Genzyme. Additional co-authors
of the study are first authors Hidekiko Nakanishi, MD, and Takahiro
Sigiura, MD, PhD, of MGH Anesthesia and the CVRC, and Scott Lonning,
PhD, of Genzyme. The study was supported by a Genzyme - Partners
HealthCare Award for Translational Research.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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