[mtwalsh01]

Blood disorders and Tmprss6

The proposed development of Tmprss6 inhibition as a therapy for diseases such as β-Thalassemia and HFE-related hemochromatosis described in the article above arose from research on the molecular basis of iron regulation. As mentioned in the article, inappropriately low expression of hepcidin (HAMP), as occurs in β-Thalassemia, causes iron overload. Tmprss6 is a serine protease which acts as a regulator of the HAMP activation pathway. Normally, Iron activates HAMP expression via the BMP receptor/SMAD pathway. Tmprss6 acts to block HAMP up-regulation by cleavage of the BMP co-receptor hemojuvelin, thus regulating iron absorption. In the study mentioned in the article, antisense oligonucleotides were used to target Tmprss6 in mouse models of β-Thalassemia and hemochromatosis, leading to amelioration of symptoms. This built on previous studies, for example a study from the Scripps Research Institute in the USA. In this study a mouse model of anaemia called ‘mask’ showed reduced absorption of dietary iron caused by high levels of hepcidin due to a splicing defect in Tmprss6. Overexpression of normal TMPRSS6 protein suppressed Hamp transcription via proximal promoter element(s). Thus TMPRSS6 was identified as an essential part of the pathway that detects iron deficiency via effects on Hamp transcription. Another study from the Vita-Salute San Raffaele University in Milan, Italy showed that homozygous loss of Tmprss6 in a mouse model called Hbb(th3/+) with a thalassemic phenotype resulted in improvement of the anemia and reduction in ineffective erythropoiesis, splenomegaly, and iron loading in these mice. Thus this paper provided proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in conditions such as β-Thalassemia. The promise of these studies has been further confirmed in the study referred to in the original article in this thread.

Sources

DU, X. et al., 2008. The serine protease TMPRSS6 is required to sense iron deficiency. Science (New York, N.Y.), 320(5879), pp. 1088-1092
GUO, S. et al., 2013. Reducing TMPRSS6 ameliorates hemochromatosis and ß-thalassemia in mice. The Journal of clinical investigation, 123(4), pp. 1531-1541
NAI, A. et al., 2012. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of ß-thalassemia. Blood, 119(21), pp. 5021-5029