Sep. 1, 1999 GAINESVILLE, Fla.---In an early test of breakthrough technology, University of Florida researchers have begun the first pilot study to determine whether the milk of genetically modified sheep can help people prone to life-threatening lung problems caused by a specific protein deficiency.
PPL Therapeutics of Edinburgh, Scotland, the lead company involved in the development of Dolly the cloned sheep, uses recombinant DNA technology - in which a gene from one organism is inserted into the DNA of another - to create "transgenic sheep" that produce the human protein alpha-1-antitrypsin, or AAT. The protein is then extracted from the milk.
Within the past 10 days, six patients whose bodies manufacture inadequate amounts of AAT, leaving them vulnerable to emphysema, have begun receiving inhaled doses of it at Shands at UF teaching hospital.
If the technique proves successful in this and larger controlled trials, a vast new source of AAT, at a sharply reduced price, potentially would be available to treat the estimated 100,000 Americans who have a deficiency of the protective protein that helps to keep lung inflammation and damage in check.
Such a new supply is critical: Currently, only a limited amount is available through blood plasma donations, so many eligible candidates must do without the therapy, which is delivered intravenously at an estimated cost of $60,000 to $80,000 annually per patient.
"I have great hopes that this will be the cornerstone therapy for this disease," said Dr. Mark Brantly, lead investigator for the study and a professor of medicine, and molecular genetics and microbiology at UF's College of Medicine.
"It could be the major 'bridge' treatment before we advance to gene therapy for this disorder," said Brantly, who also is affiliated with UF's new Genetics Institute, which is exploring such possibilities with grant support from the National Institutes of Health.
"One of the primary reasons for creating the Genetics Institute was to translate new technologies like this into treatment for patients," said Dr. Terry Flotte, interim director of the institute. "This protein therapy and anticipated gene therapy for this disorder are prime examples of what we are trying to do."
Discovered in 1963, AAT deficiency often is misdiagnosed as asthma or chronic obstructive pulmonary disease because of a lack of awareness in the medical and lay community. Fewer than 5 percent of affected individuals are diagnosed and often not until they are in their mid- to late 30s, after extensive lung damage has caused profound disability. The median age of survival is 54.
AAT is an important protein produced by the liver that protects the lungs from destructive actions of a common enzyme that normally fights bacteria and cleans up dead lung tissue. A person with the disorder, which develops in those who inherit one abnormal gene copy from each parent, does not generate enough of the protein to adequately protect the lungs, and permanent and irreversible lung damage results.
While precise figures are not available at this early stage, AAT derived from sheep is expected to be priced significantly below that of the human plasma variety.
"With transgenic drugs, there is the potential to create an enormous supply, to simply expand the flock as needed," said Brantly, whose research program has been supported by grants from the Alpha One Foundation, a Miami-based nonprofit.
"This represents a look at the future of pharmaceutical production," said Paul Doering a distinguished service professor in UF's College of Pharmacy. "We have had for a number of years now human insulin produced by genetically altered bacteria, but transgenic drugs from larger animals are extremely new and exciting and open up many topics for discussion. The future will tell how the public reacts to these sorts of developments."
Brantly's study was approved by UF's Institutional Review Board as well as by the U.S. Food and Drug Administration. The U.S. Department of Health and Human Services recently recommended that when technologically feasible, human plasma proteins should be produced through recombinant DNA technology to prevent the transmission of human blood-borne diseases. The sheep that produce AAT are quarantined to prevent them from being exposed to infections.
Doering said it is difficult to say how many tests of medicines from transgenic animals are under way, because many companies keep early trials under wraps for competitive reasons.
The transgenically produced human AAT also is being tested in cystic fibrosis patients. UF's is the first study in the world to try it in those born with AAT deficiency, according to Brantly.
Brantly, who has been researching AAT deficiency for 15 years, said his study is the first trial in which transgenic human AAT is delivered in aerosol form to those suffering from the deficiency. Such a system, Brantly noted, allows patients to treat themselves at home. The aerosol form also targets the protein to the lungs where it is needed; by contrast, the intravenous method requires significantly more product because most of the protein gets taken up in places other than the lungs.
John Walsh, chief executive officer of the Alpha One Foundation, called the UF study "extremely exciting."
"We have a critical worldwide shortage of the protein product," said Walsh, whose organization has been a driving force in coordinating efforts by scientists, government officials and pharmaceutical industry representatives to help those with the disorder. "Finding other sources is of crucial importance."
One of the first patients to receive the experimental therapy at Shands at UF is Ken Richmond, 38, a real estate agent from Fairfax Station, Va.
"I'm normally very stoic, but I'm quite excited about this study," Richmond said. "I think it's breaking new ground, and I'm honored to be a part of this group."
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