| STUDY |
The common antibiotic tetracycline and the tetracycline derivative doxycycline reduce the infectivity of prions and make prion aggregates in the brain more susceptible to enzymatic breakdown, according to a new study. The findings suggest that the drugs might provide a relatively nontoxic means of treating prion-related diseases: transmissible spongiform encephalopathies (TSEs). In TSEs, the normal brain protein PrPC (prion protein cellular) is converted to an abnormal, protease-resistant variant, PrPSc (prion protein scrapie), which forms insoluble deposits that damage brain tissue, causing disability and death. If a drug could make PrPSc more vulnerable to proteases, such deposits might be broken down by endogenous enzymes in the brain, perhaps leading to improvements in the condition of TSE patients. Researchers now find that tetracycline and doxycycline have just that kind of activity: They make prions more sensitive to proteases. The scientists find that the two drugs reduce the protease resistance of PrPSc dose-dependently: The more antibiotic they add, the less protease resistance they observe. They also show that when mixtures of either tetracycline or doxycycline with PrPSc are injected into animals, the animals stay healthy longer and have a greater tendency to remain completely disease-free than animals treated with PrPSc preparations to which the antibiotics have not been added. The therapeutic potential of most anti-TSE agents identified earlier "is limited, primarily because of inability to cross the blood-brain barrier and/or severe toxicity. On the other hand, some tetracycline derivatives such as doxycycline do pass the blood-brain barrier and reach the brain, where prion diseases do their primary damage. And tetracyclines are relatively nontoxic, well characterized pharmacologically, and (in some cases) already approved for human use. However, a number of major challenges would have to be overcome before tetracyclines, or any other drugs for that matter, can be developed as practical prion-disease therapeutics. Most drugs are unlikely to work in advanced cases of human TSEs, in which considerable damage has already been done to the brain, and no diagnostic tests are currently available to detect TSEs at an early stage, when drugs should ideally be administered. In addition, it is extraordinarily difficult to conduct double-blind clinical trials on anti-TSE agents, even if prion diseases could be diagnosed at an early stage, because human TSE cases are so rare. THE NEW FINDINGS thus serve to highlight how simple and accurate TSE diagnostic tests could help lead not only to earlier diagnoses, but also to treatments for prion diseases. Several groups are endeavoring to develop such tests. If one were to become available, then at that point maybe tetracyclines and other anti-TSE agents could be useful. "We will try to organize a trial of the tetracyclines," he says. Realistically, he concedes that tetracyclines may not be sufficiently powerful anti-TSE agents to actually stop the disease. "But maybe there is the possibility of slowing down the process," he says |
| UPDATE | 08.02 |
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