NIAID grantee Anne Lenaerts, Ph.D., and her colleagues at Colorado State University are finding new ways to speed the movement of potential TB drugs from the lab to the clinic. The scientists developed two rodent models of the disease—mouse and guinea pig—each with its own advantages.
Testing potential TB drugs in ordinary lab mice can take up to 6 months, notes Dr. Lenaerts. Not only does the disease take many weeks to develop after the animals are exposed to TB-causing bacteria, but the candidate drug must be administered for weeks or months before scientists detect evidence of its activity.
To widen this bottleneck in the drug development pipeline, Dr. Lenaerts and her co-investigators use mice that lack a gene for an important immune system molecule. The mutant mice are exceptionally susceptible to TB and develop the disease in less than 3 weeks. The Colorado researchers use the immune-compromised mouse model to quickly determine the potential anti-TB effects of candidate drugs.
According to Dr. Lenaerts, indications of efficacy can be detected in this mouse model after only 1 week of treatment with an experimental compound. Moreover, the amounts of candidate drugs needed to run the tests in immune-deficient mice are much smaller than the amounts needed in standard mouse models. This is important, she notes, because it is often difficult for chemists to make sizable quantities of new compounds early in the drug development process.
When people are infected with TB bacteria, they develop the characteristic lung formations known as granulomas, which wall off the bacteria and cause spots to be visible through medical imaging (like X-rays). But when mice are exposed to TB-causing bacteria, their illness develops differently than in people—meaning that the model does not mimic human disease as well as researchers would like. For example, mice do not develop the same type of granulomas that are seen in human infections with tuberculosis bacteria.
Granulomas are formed after TB bacteria establish a foothold in the lung. As part of the immune system reaction to infection, various immune cell types gather around TB-infected cells and wall them off from uninfected tissue. This prevents the infection from spreading and becoming active TB disease. However, not all of the TB bacteria inside a granuloma die. Destroying these so-called persistent bacteria with standard TB drug regimens is very difficult and is one reason why treatment for TB can last for months.
To gain a better understanding of the dynamics of latent (persistent) TB infection, Dr. Lenaerts uses guinea pigs. Guinea pigs develop lung granulomas which are more like the granulomas found in human TB patients. One discovery made by Dr. Lenaerts and her colleagues was the precise location of persisting bacteria around the rim of the granulomas in guinea pig lungs. Using an experimental drug, the researchers were able to nearly eliminate all of the persistent bacteria in this region of the granuloma. The finding opens the possibility that guinea pigs can serve as a means to test newly developed drug candidates aimed specifically at persistent TB bacteria. If such drugs could be identified, they could greatly shorten the time needed to cure people of TB infection.
Colorado State University is home to one part of the Tuberculosis Antimicrobial Acquisition and Coordinating Facility, an NIAID-funded research resource that evaluates compounds for possible anti-TB effects. Since 1994, some 85,000 compounds submitted to the facility have been screened (at no charge to the supplier) to determine whether they are active against TB-causing bacteria. At Colorado State, compounds shown to be active in test tube studies are tested in animals. In the past 7 years, says Dr. Lenaerts, her team has tested more than 250 compounds in mice or guinea pigs. Of these, twelve warranted continued development. Currently, two compounds that were originally tested through the Colorado facility’s animal models are being refined and further advanced by the commercial suppliers, and may one day lead to better treatments for people with TB.
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Last Updated July 14, 2009