Accession Number : ADA612000


Title :   New Drugs for Anemia Treatment Based on a New Understanding of the Mechanisms of Stress Erythropoiesis


Descriptive Note : Annual rept. 1 Sep 2013-31 Aug 2014


Corporate Author : WHITEHEAD INST FOR BIOMEDICAL RESEARCH CAMBRIDGE MA


Personal Author(s) : Lodish, Harvey


Full Text : http://www.dtic.mil/get-tr-doc/pdf?AD=ADA612000


Report Date : Sep 2014


Pagination or Media Count : 10


Abstract : We showed that the human reticulocytes made in our culture system have a hemoglobin concentration and types and major membrane proteins are identical to those in adult human red cells; these reticulocytes are as stable when transfused into NOD-SCID immune deficient mice as are normal human red cells, We completed an additional screen of 30 compounds known to activate or inhibit nuclear receptors other than the glucocorticoid receptor, and showed that two PPAR receptor agonists, fenofibrate and GW7647, potently synergized with dexamethasone in stimulating self-renewal of human and murine BFU-E progenitors and in stimulating 3- fold the output of human red cells in culture. We showed that knocking down expression of rps19 at the end of the initial expansion phase of our CD34+ cell culture system inhibited cell proliferation about 10 fold, as expected, and that GW7647 stimulated red cell production in these knockdown cells 3- fold. We also showed that the clinically tested Amgen prolyl hydroxylase inhibitor stimulated red cell production in cultures of human CD34+ stem/progenitor cells at extremely low concentrations, and that GW7647 synergized with the Amgen prolyl hydroxylase inhibitor to provide additional stimulation of red cell production in these cultures; this suggests that a combination of these two FDA- approved drugs could be used to treat certain bone marrow failure disorders. We showed that the PPAR agonist GW7647 stimulates red cell formation in Nan (neonatal anemia) mice, raising the level of red cells to almost normal. It also causes an increase in the numbers of splenic BFU-E progenitors, suggesting that GW7647 increases erythroid output via promoting BFU-E self-renewal.


Descriptors :   *ANEMIAS , *DRUGS , *ERYTHROPOIESIS , BLOOD CELLS , ERYTHROPOIETINS , RETICULOCYTOSIS , STEM CELLS


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE