Jan. 6, 1999 CHAPEL HILL - Using gene therapy on experimental animals, researchers at the University of North Carolina at Chapel Hill and elsewhere have partially corrected the protein deficiency responsible for hemophilia B. The inherited illness, also known as Christmas disease, causes victims to bleed spontaneously, live severely restricted lives and often die prematurely.
Tests have shown that a unique strain of North Carolina hemophiliac dogs injected with corrected genes produced the blood clotting protein known as factor IX and are continuing to produce it steadily more than a year and a half after treatment, scientists say. Not making the clotting factor is what causes people and animals with the condition to bleed.
"The correction is modest, about 1 percent, but we believe that's enough to justify consideration of clinical trials in humans," said Dr. Timothy C. Nichols, associate professor of medicine and pathology at the UNC-CH School of Medicine. "This level of correction in humans could be enough to improve certain people with severe hemophilia, who bleed spontaneously, to the point where they would only bleed when injured. That would be a major improvement."
Two reports on the research appear in the Jan. 5 issue of Nature Medicine. Besides UNC-CH, other institutions involved include the universities of Pennsylvania and Washington at Seattle, Stanford University and biotechnology companies Avigen Inc. and Cell Genesys Inc. of Alameda and Foster City, Calif., respectively.
The dogs, which inherit hemophilia naturally just as humans do and have been bred for a half century at UNC-CH's Frances Owen Blood Research Laboratory, showed a dose response, Nichols said. That is, the more corrected gene they received, the more strongly their bodies responded. They tolerated the treatment and replacement therapy well.
"This dose response should identify the appropriate initial dose for use in humans," he said.
One report describes experiments in which corrected genes were injected into the dogs' muscles. The other involved injections into blood vessels leading to the liver, where factor IX is made normally.
"We and Dr. Katherine High of Penn reasoned that if you could just give patients a shot into muscle, gene therapy could work with little or no sedation, and it would be easier to get a clinical trial going and easier on patients." Nichols said. "We think the new work tends to confirm that."
Both studies employed a flu-like virus that had been rendered harmless as a vector to carry the corrected genes into muscle or liver cells where they could begin producing factor IX, he said.
Hemophilia B affects up to about 5,000 people in the United States and possibly 10 times that many worldwide, Nichols said. Currently, sales of an artificially produced factor IX that requires regular injections are between $500 million and $1 billion dollars annually, and that does not include treatment costs.
"From an expense point of view, the total cost of treating these patients is just extraordinary, especially when you think of it over a lifetime," he said. "The new work suggests that it's conceivable that appropriately selected patients could come into a clinic, get one or more shots that take less than an hour to administer and still be making clotting factor a year or two later. That would have a huge beneficial impact both for patients, who now have to come in several times a month, and their health-care costs."
Because of its hemophiliac dogs, the Frances Owen Blood Research Laboratory in UNC-CH's department of pathology and laboratory medicine, is a unique national and international medical research resource established by Dr. Kenneth M. Brinkhous, professor of pathology emeritus, and colleagues in the late 1940s. Previous forms of therapy for hemophilia, such as synthetic clotting factors, which worked in the dogs, also have worked in humans.
Besides Nichols and Brinkhous, UNC-CH authors of the reports include Drs. Hui-Feng Lin, Darrel W. Stafford, Marjorie S. Read and Dwight A. Bellinger and medical student Dan Elwell.
Hemophilia A, a different form of the illness caused by inadequate factor XIII production, is about five times as common as hemophilia B. Brinkhous and colleagues discovered and described factor XIII in the 1940s, developed the widely used partial thromboplastin time (PTT) test for detecting blood clotting disorders and developed a clotting factor concentrate, which was the first effective treatment for hemophilias.
The team plans to conduct comparable studies in UNC-CH hemophilia A dogs soon.
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