MTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease. (31st March 2016)

• Record Type: Journal Article
• Authors: Wang, Jintao; Tran, Jennifer; Wang, Hui; Guo, Chiao; Harro, David; Campbell, Andrew D.; Eitzman, Daniel T.
• Is Part Of: British journal of haematology. Volume 174:Number 3(2016)
• Page Start: 461
• Page End: 469
• Publication Date: 2016-03-31
• Subjects: mechanistic target of rapamycin -- anaemia -- sickle cell disease -- sirolimus -- stroke; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.14057
• Languages: English
• ISSNs: 0007-1048

Abstract

Abstract : Mechanistic target of rapamycin (mTOR) has been shown to play an important role in red blood cell physiology, with inhibition of mTOR signalling leading to alterations in erythropoiesis. To determine if mTOR inhibition would improve anaemia in sickle cell disease (SCD), mice with SCD were treated with the dual mTORC1/2 inhibitor, INK128. One week after daily oral drug treatment, erythrocyte count, haemoglobin, and haematocrit were all significantly increased while reticulocyte counts were reduced. These parameters remained stable during 3 weeks of treatment. Similar effects were observed following oral treatment with the mTORC1 inhibitor, sirolimus. Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice. Following middle cerebral artery occlusion, stroke size was reduced in SCD mice treated with sirolimus. In conclusion, mTOR inhibition is protective against anaemia and organ damage in a murine model of SCD.