DEVELOPMENT OF DRUGS FOR CRYPTOSPORIDIUM INFECTION

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Current therapies to treat opportunistic infections associated with the Acquired Immunodeficiency Syndrome (AIDS) are either highly toxic, extremely expensive or marginally effective. Since these infections produce significant morbidity and mortality in patients with AIDS, the National Institute of Allergy and Infectious Diseases has funded several programs to facilitate discovery and development of novel therapies for the treatment of AIDS-related opportunistic infections. Within the Developmental Therapeutic Branch, this has been accomplished by providing contract resources for identifying and developing potential new drugs. At present there is no recommended therapy for infection with Cryptoslporidium parvum, in part, because of the lack of in vitro culture systems and small animal models that are suitable for drug evaluations. Phase 1 of this project will support three agencies in the development of in vitro and in vivo test systems. Thereafter in Phase 2 of the program, one or more of these agencies will be selected to apply their systems toward evaluating the efficacy of potential new drugs against Cryptosporidium. The culture systems and animal models developed through these contracts will therefore provide NIAID with the necessary resources to provide critical support for investigator-initiated drug discovery, to stimulate private sector sponsorship of compounds with demonstrated efficacy, and to select the best drug candidates for clinical trials. Phase I of the contract indicated above will develop and validate the dexamethasone (DEX)-suppressed C57BL/6N mouse as a model for chronic cryptosporidiosis. If selected for Phase 2 of the program the contractor will utilize the DEX mouse model to screen pharmacologic agents active against Cryptosporidiosis, and furthermore conduct initial toxicity and pharmacokinetic assessments and optimize drug dosages and delivery routes. The contractor will furthermore test various cell lines in their ability to support parasite growth in vitro and perform initial compound screening against the parasite.