Iron has important physiological roles including oxygen transport and is an important cofactor for many different enzymes. The body has developed a complex signaling system to regulate iron levels by tightly controlling iron absorption in the gut, as high levels of iron can be toxic to cells.

Iron overload disorders, such as the common genetic disorder hereditary hemochromatosis, are characterized by errors in iron regulation leading to a chronic life long hyperabsorption of iron. Overtime, this hyperabsorption results in a large increase in iron stores and toxic free iron within the body eventually causing liver toxicity and damage to multiple organs. One in 300 individuals of North European descent carry the hereditary hemochromatosis gene (HFE) and are programmed to have iron overload typically by the fifth decade.

Xenon is developing small molecule inhibitors of DMT1 as a treatment for iron overload disorders. Genetic studies have demonstrated DMT1’s essential role in iron hyperabsorption. Additional studies showed that genetically defective DMT1 is able to block iron overload in a model of hereditary hemochromatosis (HFE knockout).

Furthermore, in human patients with hereditary hemochromatosis the DMT1 gene is over represented in the gut lining, validating its key role in iron hyperabsorption in the human disease.

We propose that small molecule inhibitors of DMT1 would block the iron hyperabsorption seen in hereditary hemochromatosis and other disorders of iron overload.

Xenon has developed significant drug discovery technologies to support our iron overload program. We have a proprietary HTS screening assay which has identified the first small molecule inhibitors for this class of target. These inhibitors are presently advancing through lead optimization and have already demonstrated in vivo efficacy in established models of iron hyperabsorption.

Our Iron Overload Program receives funding support from Genome BC and Genome Canada.