Oral Formulation of Zonulin Antagonist AT-1001 for Diabe

DESCRIPTION (provided by applicant): The trigger for autoimmune destruction of pancreatic beta cells in Type 1 diabetes (T1D) is unclear. Evidence exists for the role of increased intestinal permeability, secondary to intestinal tight junctions (tj) disassembly, in the pathogenesis of various autoimmune diseases including T1 D. Over the last decade our studies have focused on the mechanism(s) of action of a protein elaborated by Vibrio cholerae, zonula occludens toxin (Zot) that reversibly opens the intestinal tj. These findings led to the discovery of zonulin, a human eukaryotic Zot analogue involved in the pathogenesis of T1D, and to the synthesis of a synthetic peptide zonulin inhibitor (AT-1001). In both an animal model of diabetes (BB/wor rats) and in patients affected by T1D we have demonstrated an association between serum zonulin levels and intestinal permeability. In BB/wor rats, we were able to prevent the onset of T1D and block ICA seroconversion by oral administration of AT-1001. Based on the above data, we have established as our long-term objective the development of AT-1001 as an oral agent for the mitigation of continued beta-cell destruction in newly diagnosed T1D patients ("beta cell rescue"). The proposed studies will generate critical information that will be used to develop innovative strategies for the prevention and early treatment of T1D and other autoimmune diseases characterized by a zonulin-dependent increase in intestinal permeability. Specifically, we propose: AIM 1. To assess the "drugability" of AT-1001 AIM 2. To develop bioanalytical methods for measuring AT1001 and its physiologic effect AIM 3. To perform Pharmacodynamic and Pharmacokinetic Studies with AT100 AIM 4. Develop optimal oral formulations for AT-1001