Grant: Project Grant

Preterm birth (PTB) and fetal inflammation (FI) are the major perinatal causes of mortality in children <5 years and of life-long morbidity. These are caused by maternal inflammation or infection and can lead to the arrest of fetal organ development and death. A key mediator for these events is interleukin (IL)6. We have synthesized a very specific allosteric peptide antagonist to the IL6 receptor, HSJ633 (sequence: VRKFQNSPA), that is highly effective in preliminary experiments in blocking PTB and FI due to infectious stimulants. We hypothesize that HSJ633 is a safe and efficacious therapeutic for preventing PTB and FI. Our objective is to understand better the pharmacology and toxicology of HSJ633. We will use sophisticated methodology to discern how HSJ633 selectively blocks molecular and cellular mechanisms of the IL6 receptor and specifically the STAT3 intracellular signaling pathway. Next, we will test whether HSJ633 antagonizes IL6 actions in human fetal membranes to prove that it works in humans. Then, we will continue testing various doses HSJ633 in mouse models to determine its optimal dosage. To demonstrate it is pharmacologically superior, we will compare it to the established monoclonal antibody antagonist to IL6, Tocilizumab (TOC), which is FDA approved for rheumatoid arthritis. To demonstrate its safety, we will test the toxicology of HSJ633 in two generations of mice to show that fetal exposure does not impair offspring growth and reproduction. An exhaustive examination of fetal organs will be made. Last, we will test the efficacy of HSJ633 in a chronically inflamed pregnant mouse model using low dose LPS to ascertain whether it blocks FI. Together these tests will confirm that IL6 is a key target for blocking PTB and FI, that HSJ633 is effective and safe, and is a therapeutic that should undergo more rigorous testing for its clinical and commercial potential.