Accession Number : ADA612373


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


Descriptive Note : Annual rept. 1 Sep 2012-31 Aug 2013


Corporate Author : WHITEHEAD INST FOR BIOMEDICAL RESEARCH CAMBRIDGE MA


Personal Author(s) : Lodish, Harvey


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a612373.pdf


Report Date : Sep 2013


Pagination or Media Count : 33


Abstract : We have completed and exceeded both of the goals for the first year of this project. The first goal was determining the optimum combination and concentrations of clinically-tested prolyl hydroxylase inhibitors (PHIs) and glucocorticoid receptor agonists and dissociated agonists that act on murine BFU-E progenitors in culture to increase the output of erythroid cells. We have shown that very low concentrations of both Amgen s and FibroGen's clinical- grade Prolyl Hydroxylase Inhibitors (PHIs) targeting the PHD2 enzyme synergize with very low concentrations of the corticosteroid dexamethasone in stimulating self renewal and increasing the output of both murine and, importantly, human erythroid cells. We completed the second goal - screening of a library of 2000 tested and approved therapeutic drugs and some novel molecules for additional compounds that stimulate red cell production in culture, either at the BFU-E or CFU-E level and identified 45 potential hits. We chose 12 for detailed characterization, and showed that four non-steroid drugs and 6 steroid drugs, all approved by the FDA for other indications, stimulate expansion of murine BFU-E progenitors in culture and stimulate red cell production to the same extent as the corticosteroid dexamethasone. We have focused on one cimetidine (Tagamet) - and showed that it and three other FDA-approved Histamine H2 receptor antagonists stimulate BFU-E self-renewal and increase the output of both murine and, importantly, human erythroid cells in culture. Following additional experiments to characterize the red cells formed in these cultures of human blood CD34+ hematopoietic stem and progenitor cells, these and other approved drugs should be poised to enter clinical trials for Diamond Blackfan anemia and other bone marrow failure disorders.


Descriptors :   *ANEMIAS , *DRUGS , *ERYTHROPOIESIS , BLOOD CELLS , RECEPTOR SITES(PHYSIOLOGY)


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE