2. Academic Validation
  3. The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice

The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice

  • Blood. 2015 Jul 16;126(3):386-96. doi: 10.1182/blood-2015-02-626259.
Shuaiying Cui 1,  Kim-Chew Lim 1,  Lihong Shi 1,  Mary Lee 1,  Natee Jearawiriyapaisarn 1,  Greggory Myers 1,  Andrew Campbell 2,  David Harro 3,  Shigeki Iwase 4,  Raymond C Trievel 5,  Angela Rivers 6,  Joseph DeSimone 7,  Donald Lavelle 7,  Yogen Saunthararajah 8,  James Douglas Engel 1
Affiliations

Affiliations

  • 1 Department of Cell and Developmental Biology.
  • 2 Department of Pediatrics and Infectious Diseases.
  • 3 Department of Pathology.
  • 4 Department of Human Genetics, and.
  • 5 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI;
  • 6 Jesse Brown VA Medical Center, Department of Pediatrics, and.
  • 7 Department of Pediatrics, and Department of Medicine, University of Illinois at Chicago, Chicago, IL; and.
  • 8 Cleveland Clinic, Cleveland, OH.
PMID: 26031919 DOI: 10.1182/blood-2015-02-626259
Abstract

Inhibition of lysine-specific demethylase 1 (LSD1) has been shown to induce fetal hemoglobin (HbF) levels in cultured human erythroid cells in vitro. Here we report the in vivo effects of LSD1 inactivation by a selective and more potent inhibitor, RN-1, in a sickle cell disease (SCD) mouse model. Compared with untreated Animals, RN-1 administration leads to induced HbF synthesis and to increased frequencies of HbF-positive cells and mature erythrocytes, as well as fewer reticulocytes and sickle cells, in the peripheral blood of treated SCD mice. In keeping with these observations, histologic analyses of the liver and spleen of treated SCD mice verified that they do not exhibit the necrotic lesions that are usually associated with SCD. These data indicate that RN-1 can effectively induce HbF levels in red blood cells and reduce disease pathology in SCD mice, and may therefore offer new therapeutic possibilities for treating SCD.

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