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 facilitates discovery and development of novel therapies for the treatment of AIDS-related opportunistic infections. This includes providing contract resources for identifying and developing potential new drugs, and conducting efficacy evaluations in animal models, a critical component in the drug approval process. At present there is no recommended therapy for infection with Cryptosporidium 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 1 of the contract indicated above will adapt the SCID mouse for in vivo screening of candidate therapies against Cryptosporidium infection. Criteria for evaluating the impact of pharmacologic agents include: oocyst shedding, tissue colonization (distribution and intensity) and clinical signs. The SCID mouse model will be further adapted to evaluate agents in a 4-tiered assay protocol employing 1) a prophylactic model, 2) a chronic model, 3) a terminal/disseminated model, and 4) a relapsing/recurrent model. If selected for Phase 2 of the program, the contractor will 1) systematically apply their animal model toward drug evaluations 2) develop a reproducible, quantitative model of C. parvum cultivation in vitro, and 3) apply the culture assays to initially screen compounds for further testing-in the SCID model.
