Abstract

Our project focuses on developing a novel treatment for hematological disorders caused by an iron overload, such as hemochromatosis and thalassemia. These autosomal recessive disorders have symptoms including cirrhosis, arthritis, and heart failure, which result from overabsorption of iron from the duodenum. Although these are among the most common heritable diseases, treatment options are limited. Even today patients are mostly treated by frequent bloodletting, which many people cannot support. The aim of our project is to combat these diseases at the source by developing a therapy that prevents the intestinal absorption of iron.

We engineer the Escherichia coli Ferric Uptake Regulation (FUR) system using a genetic inverter so that they produce siderophores (iron chelators) in response of high concentrations of iron. These engineered bacteria are delivered to the patient's intestine by encapsulating them in an ingestible polymer (capsule) that specifically degrades in the duodenum. Once released into the intestine, the bacteria respond to ambient iron by secreting elevated levels of siderophores, thereby chelating the iron to prevent its absorption by the patient.

The Iron Coli Project deals with iron, and more precisely about the most frequent genetic disease related to that ion, hemochromatosis. In our human body, iron is essentially found under a hemic structure. For example, iron is bound to hemoglobin inside red cells to transport oxygen. Also, iron bound to cytochrome carry the function of detoxification in the liver but also energy production by the mitochondria.
So iron is essential to our human body for many metabolic pathways. In fact, it is finely regulated in our human body and unfortunately, the unbalance of this smooth regulation leads has dramatic consequences. Our human body has a total pool of 4000 mg of iron. Every day, we absorb 1 mg by the upper intestine (duodenum and jejunum) and excrete 1 mg by tissue renewel (intestin, skin, hair, bleeding, etc...). However, a hemochromatosic patient absords on average 4 times more iron. On a long term, this patient accumulates the iron which is very toxic in its free form. The only mechanism we have to decrease the blood level of iron is to store it in our tissues. Heart, liver, kidneys, muscles, all these organs start to store the iron, which enhances its toxicity. This