NEW YORK, Feb 17 (Reuters Health) -- A novel approach to treating children
with alpha1-antitrypsin deficiency, the most common genetic liver disease, is
being studied by researchers at the Washington University School of Medicine in
St. Louis.
The proposed treatment involves using a drug to force mutant forms of a
protein out of cells. Once in the blood, this protein can help correct problems
caused by the gene defect.
Alpha1-antitrypsin (alpha1-AT) is a protein normally produced by the
liver. Its primary function is to inhibit the action of the enzyme, trypsin.
When alpha1-AT is deficient, tissue damage results from the destructive effects
of uncontrolled trypsin. Severe lung and liver complications follow.
According to Dr. Jon A.J. Burrows and colleagues at the Missouri medical
institution, in individuals deficient in the protein, a functional variant of
alpha1-AT is actually produced, but is trapped in the liver cells and fails to
reach the blood stream. The research team theorized that this genetic mutant
would be of therapeutic value if it could be released from liver cells.
Writing in the February 15th issue of the Proceedings of the National
Academy of Sciences, the study authors describe how so-called 'chemical
chaperones' can foster "a marked increase in secretion of (the) functionally
active" mutant form of alpha1-AT, called alpha1-ATZ.
It is known that chemical chaperones can effectively modify a defective
protein by making structural changes to it. A number of potential chemical
chaperones have been suggested and investigated in relation to other disorders.
In the current study, the team used cells grown in the lab and mice
especially bred to carry the human alpha1-ATZ gene to demonstrate how chemical
chaperones can successfully increase secretion of usable alpha1-AT. One of these
chemicals, called 4-phenylbutyric acid, or PBA, was used both on the
experimental cells and the mice.
"There was an increase in... alpha1-AT levels during PBA treatment in
every single mouse," the researchers report. Similar results were achieved in
the cell culture work.
The team also experimented with glycerol, a sugar alcohol that is an
important component of many fatty compounds. They found that it, too, "mediates
a significant increase in the secretion of... alpha1-ATZ" in cultured cells.
Burrows and his team believe that "chemical chaperones -- particularly PBA
-- satisfy many of the criteria required for a potential (preventive) strategy
(against) liver and lung injury" in alpha1-AT deficiency.
"This approach eventually could prevent these patients from needing liver
or lung transplants," said senior study author Dr. David H. Perlmutter in a
statement.
He added that similar treatment might also help patients with other
diseases, including Alzheimer's, Parkinson's and Huntington's disease.
"I think this approach could ultimately have a major impact on a number of
disorders," noted Perlmutter.
