Polyamine based Therapy of E. bieneusi Infected Mice

DESCRIPTION (provided by applicant): The microsporidia Enterocytozoon bienusi is the principal agent of enteric infections in immunocompromised patients. The most common manifestation is gastrointestinal tract infection; however, encephalitis, ocular infection, sinusitis, myositis and disseminated infection are reported. Until now it was difficult to find an appropriate model for therapeutic studies with this parasite, since it cannot be cultured in vitro, and it does not cause murine infections that can be used as a model. However, Dr. Tzipori's groundbreaking work with SCID mice opened the possibility to assess the efficacy of the polyamine analogs we developed to control murine microsporidosis in a model that is relevant for human infections. Dr. Tzipori demonstrated that persistent E. bieneusi infections in SCID mice could be readily induced with isolates of human origin. We will develop synthetic procedures amenable to scale-up to prepare three polyamine analogues; namely, SL-11158, SL-11157, and SL-11302. SL-11158 was shown to be very efficacious in suppressing murine microsporidiosis caused by E. cuniculi infection when administered i.p. However, it will be tested orally to mimic the future treatments of patients in the SCID mice model along with SL-11157, and SL-11302. In our bioavailability studies of SL-11158 in rats and dogs the oral bioavailability was minimal, prompting us to add SL-11157 to the study which is a stereoisomer of SL-11158. SL-11157 and SL-11302 were efficacious in suppressing tumor growth in vivo when given orally to mice suggesting a better oral bioavailability. The synthetic polyamine analogs will be administered by the oral route to the E. bieneusi infected SCID mice and the therapeutic effects of each drug will be assessed, and the best drug will be chosen for preclinical trials.