Using a small molecule iron transporter to understand and treat FPN1 deficiencies in mice

点击翻译按钮获取中文摘要

1. Project Summary / Abstract This project aims to develop a “molecular prosthetics” approach for treating diseases caused by genetic or acquired deficiencies of the iron transporting protein ferroportin (FPN1), known as Ferroportin disease and Anemia of Inflammation, respectively. Loss of function of FPN1 leads to anemia and/or iron retention in the liver due to deficiencies in the absorption of dietary iron into the blood and/or the recycling of iron from red blood cells. This includes a small population of genetically well-characterized patients with loss-of-function mutations in FPN1, as well as >10 million patients with autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, Celiac disease, and systemic lupus erythematosus, who suffer from acquired deficiencies of this same protein. Currently available treatments, including regular phlebotomy and blood transfusions fail to address the common underlying deficiency in FPN1 function. Highly collaborative efforts between our labs led to the discovery of a small molecule natural product isolated from the hinoki tree in Taiwan, called hinokitiol, that can autonomously transport iron across cellular membranes. We found that iron gradients build up upstream of the membranes that normally host the missing FPN1 protein, setting the stage for site- and direction-selective restoration of transmembrane iron transport by this inherently not site- and direction-selective small molecule. We also found that that this small molecule iron transporter interfaces with the robust protein-based networks that drive iron homeostasis, creating a molecular bionic-type system. Preliminary results in leading animal models of Ferroportin disease and Anemia of Inflammation are also very encouraging. Building on these frontier concepts and extensive preliminary results, we now plan to probe in depth the effects of genetic and acquired deficiencies of FPN1 in both cells and animals, extensively characterize the capacity for hinokitiol to replicate the function of the missing FPN1 protein and thereby restore physiology, and determine the safety of both acute and chronic administration of hinokitiol. These studies collectively represent a critical next step toward translating this frontier molecular prosthetics approach into a new clinical treatment for patients suffering from diseases caused by FPN1 deficiencies.