Inflammatory disorders account for a significant percentage of debilitating diseases. It is now apparent that central to the therapeutic control of the inflammatory reaction in the regulation of the phospholipid metabolites, the eicosanoids. In most tissues the synthesis of the eicosanoids is limited by the availability of arachidonic acid (AA) which is first liberated from membrane phospholipids by the activity of phospholipase A2 (PLA2). The goal of the proposed work is therefore to produce by mammalian cell expression a recombinant inhibitor of PLA2 termed anti-inflammatory protein (AIP) which we have recently cloned. The Phase II research is directed towards: 1) developing a high producing mammalian cell line producing recombinant AIP at levels suitable for pre-clinical trials in suitable acute and chronic animal models of inflammation; 2) determining the structure of smaller, active fragments which retain biological activity; 3) testing the efficacy of the fragments when delivered nasally to animals using Cal Bio's Nazdel TM delivery system. Positive results from the Phase II research should allow us to produce enough rAIP for chronic treatment so that possible side effects can be monitored and clinical trials designed. The results should result in the development of an anti-inflammatory therapeutic which does not carry the side-effects and toxicity of existing non-endogenous anti-inflammatory drugs and could be used to treat such chronic diseases as arthritis, systemic limpus and psoriasis.
