title: mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease.
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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Cardiovascular Research Center, Ann Arbor, MI, USA.
authors.forename: Jintao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tran
authors.affiliation: Department of Internal Medicine, University of Michigan, Cardiovascular Research Center, Ann Arbor, MI, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Michigan, Cardiovascular Research Center, Ann Arbor, MI, USA.
authors.forename: Chiao
authors.initials: C
authors.lastname: Guo
authors.affiliation: Chemical Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Harro
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Department of Internal Medicine, University of Michigan, Cardiovascular Research Center, Ann Arbor, MI, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Eitzman
mesh_terms: D000740:Anemia / Q000517:prevention & control; D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects; D006400:Hematocrit; D006454:Hemoglobins; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000627:therapeutic use*; D013163:Splenomegaly / Q000188:drug therapy / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D006454:Hemoglobins; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C572449:sapanisertib; D000225:Adenine
keywords: anaemia; mechanistic target of rapamycin; sickle cell disease; sirolimus; stroke