Instead of picking one target for drug screen, they focused on the symptoms of the disease
Using zebrafish, researchers at the Institute of Genomics and Integrative Biology (CSIR-IGIB) have successfully discovered a pathway that regulates hepcidin hormone production. The hepcidin hormone, released by the liver, is a central regulator of iron in the body. Dysregulation of the hormone leads to anaemia on one hand and excess iron accumulation in organs such as liver and heart leading to multi-organ failure.
Hemochromatosis is a rare hereditary disease that is characterised by iron accumulation or overload in various tissues. The symptoms are non-specific and hence difficult to diagnose. Current options only manage the disease by removing excess iron. “One method is to bleed the patients and the other is to absorb iron using iron chelation, which is toxic to liver and kidney and may also cause hearing problems. There is no therapy currently available,” says Sandeep Basu from CSIR-IGIB and first author of a paper published in ACS Chemical Biology.
Gene mutations
Mutations in about six genes are known to cause reduction in hepcidin hormone production thereby causing excess iron accumulation. But for the study, the research team led by Chetana Sachidanandan created a disease model in zebrafish (a fish exhibiting similar characteristics of the human disease) by mutating one of these genes (TFR2). Mutations in the TFR2 gene cause a severe form of the disease.
The zebrafish with the mutant gene showed excess iron accumulation in organs, quite similar to what is seen in humans.
In the conventional drug discovery approach, the target protein and even the pathway are already known and molecules that would either inhibit or overproduce the target protein are screened for. But the researchers adopted a different approach for this study.
“Hepcidin gene is controlled by many factors, many of them not well understood. So, instead of picking one target for our drug screen, we focused on the symptoms of the disease — excess accumulation of iron,” says Dr. Sachidanandan. “We knew that hepcidin hormone is low in the hemochromatosis patients, and that this causes iron overload.”
Click here to read more.
