St. Louis, Feb. 15, 2000 -- Children with the most common genetic cause of liver disease are at increased risk of developing life-threatening liver disease and emphysema. Using mice, researchers at Washington University School of Medicine in St. Louis have identified a new treatment approach that could prevent the serious complications of the disease, called alpha-1-antitrypsin deficiency.
"This approach eventually could prevent these patients from needing liver or lung transplants," said senior author David H. Perlmutter, M.D., the Donald Strominger Professor of Pediatrics and professor of cell biology and physiology.
Perlmutter and colleagues report their findings in the Feb. 15 issue of Proceedings of the National Academy of Sciences. The first author of the study is Jon A. J. Burrows, a postdoctoral fellow.
Alpha-1-antitrypsin ordinarily functions as an inhibitor of enzymes that can degrade connective tissue. People with alpha-1-antitrypsin deficiency make an abnormally folded version that gets retained inside liver cells instead of being secreted into body fluids. Emphysema is believed to result when the protein¹s absence from lung fluid allows degradative enzymes to wreak havoc. Liver injury is thought to be caused by the toxicity of the retained mutant protein.
In this study, Perlmutter and colleagues demonstrated that a drug called 4-phenylbutyric acid (PBA) improved secretion of mutant alpha-1-antitrypsin in a model cell culture system. The drug also increased levels of alpha-1-antitrypsin 20 percent to 50 percent in a transgenic mouse model. PBA belongs to a class of compounds called chemical chaperones, which get into cells and reverse protein misfolding. It already is approved by the FDA for other therapeutic purposes.
"This drug helps the mutant protein get out of the liver and into the blood and body fluids," Perlmutter said. "The mutant then can partially perform the job of the normal protein."
In one set of experiments, the researchers studied mice with two copies of the mutant human alpha-1-antitrypsin gene. When the animals were 6 to 7 weeks of age, one group was fed 14 milligrams of PBA daily for five days and the other was fed plain water. The treatments then were stopped for two days before the groups were crossed over for another seven-day period. The researchers drew blood from the mice on the day before the trial began and on days 3, 5, 8 and 12.
During treatment with PBA, human alpha-1-antritrypsin levels increased by one-third to one-half by day 3 and remained elevated for the entire five days of the PBA treatment period. The levels were down to pre-treatment levels seven days after the PBA treatment was discontinued.
Using genetically modified cells in culture, the researchers also showed that glycerol can increase the secretion of mutant alpha-1-antitrypsin.
Perlmutter said the results demonstrate that the effects of chemical chaperones, particularly PBA, satisfy many of the criteria required for prevention of liver and lung injury in alpha-1-antitrypsin deficiency. One trial in humans with alpha-1-antitrypsin deficiency has begun, and Perlmutter believes these studies will lead to several more.
Scientists also have identified many more human diseases in which chemical chaperones might be useful for treatment. Perlmutter said a similar approach might help patients with diseases such as Alzheimer¹s, Parkinson¹s and Huntington¹s.
"I think this approach could ultimately have a major impact on a number of disorders," he said.
This research was supported by grants from the National Institutes of Health.
Burrows JAJ, Willis LK, Perlmutter DH. Chemical Chaperones Mediate Increased Secretion of Mutant a1-Antitrypsin (a1-AT) Z. Proceedings of the National Academy of Sciences, vol. 97 (4), pp. 1796-1801. Feb. 15, 2000.
Copies of the paper are available from the PNAS news office (202) 334-2138, or e-mail pnasnews@nas.edu
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.
Journal
Proceedings of the National Academy of Sciences