PMID- 28880867
OWN - NLM
STAT- MEDLINE
DCOM- 20170914
LR  - 20220408
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 14
IP  - 9
DP  - 2017 Sep
TI  - Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene 
      regulation in sickle cell disease: A randomized phase 1 study.
PG  - e1002382
LID - 10.1371/journal.pmed.1002382 [doi]
LID - e1002382
AB  - BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts 
      terrible global morbidity and mortality, is driven by polymerization of mutated 
      sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) 
      interferes with this polymerization, but HbF is epigenetically silenced from 
      infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To 
      pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical 
      trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and 
      tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that 
      otherwise rapidly deaminates/inactivates decitabine, severely limiting its 
      half-life, tissue distribution, and oral bioavailability. Oral decitabine doses, 
      administered after oral THU 10 mg/kg, were escalated from a very low starting 
      level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in 
      depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early 
      death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo 
      in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of 
      follow-up. The primary endpoint was >/= grade 3 non-hematologic toxicity. This 
      endpoint was not triggered, and adverse events (AEs) were not significantly 
      different in THU-decitabine-versus placebo-treated patients. At the decitabine 
      0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and 
      remained elevated for several hours. This dose decreased DNMT1 protein in 
      peripheral blood mononuclear cells by >75% and repetitive element CpG methylation 
      by approximately 10%, and increased HbF by 4%-9% (P < 0.001), doubling fetal 
      hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total 
      RBCs. Total hemoglobin increased by 1.2-1.9 g/dL (P = 0.01) as reticulocytes 
      simultaneously decreased; that is, better quality and efficiency of HbF-enriched 
      erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating 
      better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation 
      (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved. As expected with 
      non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently 
      decreased, but not to an extent requiring treatment holds. As an early phase 
      study, limitations include small patient numbers at each dose level and narrow 
      capacity to evaluate clinical benefits. CONCLUSION: Administration of oral 
      THU-decitabine to patients with SCD was safe in this study and, by targeting 
      DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical 
      benefits and potential harms not identified to date. TRIAL REGISTRATION: 
      ClinicalTrials.gov, NCT01685515.
FAU - Molokie, Robert
AU  - Molokie R
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
AD  - Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
FAU - Lavelle, Donald
AU  - Lavelle D
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
AD  - Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
FAU - Gowhari, Michel
AU  - Gowhari M
AUID- ORCID: 0000-0002-1958-278X
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Pacini, Michael
AU  - Pacini M
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Krauz, Lani
AU  - Krauz L
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Hassan, Johara
AU  - Hassan J
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Ibanez, Vinzon
AU  - Ibanez V
AUID- ORCID: 0000-0002-0591-4894
AD  - Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
FAU - Ruiz, Maria A
AU  - Ruiz MA
AD  - Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
FAU - Ng, Kwok Peng
AU  - Ng KP
AUID- ORCID: 0000-0003-1779-556X
AD  - Translational Hematology and Oncology Research, Taussig Cancer Institute, 
      Cleveland Clinic, Cleveland, Ohio, United States of America.
FAU - Woost, Philip
AU  - Woost P
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, 
      Ohio, United States of America.
FAU - Radivoyevitch, Tomas
AU  - Radivoyevitch T
AD  - Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, 
      United States of America.
FAU - Pacelli, Daisy
AU  - Pacelli D
AUID- ORCID: 0000-0002-6609-9635
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Fada, Sherry
AU  - Fada S
AD  - Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland 
      Clinic, Cleveland, Ohio, United States of America.
FAU - Rump, Matthew
AU  - Rump M
AUID- ORCID: 0000-0002-6585-1506
AD  - Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland 
      Clinic, Cleveland, Ohio, United States of America.
FAU - Hsieh, Matthew
AU  - Hsieh M
AUID- ORCID: 0000-0002-3706-6615
AD  - Molecular and Clinical Hematology Section, National Institutes of Health, 
      Bethesda, Maryland, United States of America.
FAU - Tisdale, John F
AU  - Tisdale JF
AD  - Molecular and Clinical Hematology Section, National Institutes of Health, 
      Bethesda, Maryland, United States of America.
FAU - Jacobberger, James
AU  - Jacobberger J
AD  - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, 
      Ohio, United States of America.
FAU - Phelps, Mitch
AU  - Phelps M
AUID- ORCID: 0000-0002-1615-5280
AD  - College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of 
      America.
FAU - Engel, James Douglas
AU  - Engel JD
AUID- ORCID: 0000-0001-9593-1825
AD  - Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, 
      United States of America.
FAU - Saraf, Santhosh
AU  - Saraf S
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Hsu, Lewis L
AU  - Hsu LL
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Gordeuk, Victor
AU  - Gordeuk V
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - DeSimone, Joseph
AU  - DeSimone J
AD  - Department of Medicine, University of Illinois Hospital and Health Sciences 
      System, Chicago, Illinois, United States of America.
FAU - Saunthararajah, Yogen
AU  - Saunthararajah Y
AUID- ORCID: 0000-0002-9757-1031
AD  - Translational Hematology and Oncology Research, Taussig Cancer Institute, 
      Cleveland Clinic, Cleveland, Ohio, United States of America.
AD  - Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland 
      Clinic, Cleveland, Ohio, United States of America.
LA  - eng
SI  - ClinicalTrials.gov/NCT01685515
GR  - S10 OD021559/OD/NIH HHS/United States
GR  - P30 CA043703/CA/NCI NIH HHS/United States
GR  - R01 HL114561/HL/NHLBI NIH HHS/United States
GR  - P30 CA016058/CA/NCI NIH HHS/United States
GR  - U01 HL117658/HL/NHLBI NIH HHS/United States
GR  - K23 HL125984/HL/NHLBI NIH HHS/United States
GR  - U54 HL090513/HL/NHLBI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170907
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Enzyme Inhibitors)
RN  - 18771-50-1 (Tetrahydrouridine)
RN  - 776B62CQ27 (Decitabine)
RN  - 9034-63-3 (Fetal Hemoglobin)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Adult
MH  - Anemia, Sickle Cell/*drug therapy/genetics
MH  - Azacitidine/administration & dosage/*analogs & derivatives/pharmacology
MH  - Decitabine
MH  - Drug Therapy, Combination
MH  - Enzyme Inhibitors/*administration & dosage/pharmacology
MH  - Epigenesis, Genetic/*drug effects
MH  - Female
MH  - Fetal Hemoglobin/drug effects
MH  - Gene Expression Regulation/*drug effects
MH  - Gene Silencing/drug effects
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Tetrahydrouridine/*administration & dosage/pharmacology
MH  - Treatment Outcome
MH  - Young Adult
PMC - PMC5589090
COIS- I have read the journal's policy and the authors of this manuscript have the 
      following competing interests: DL, JD, and YS have patent applications around 
      decitabine and around the combination of tetrahydrouridine and decitabine. In 
      addition, JD and YS are consultants to EpiDestiny, that has licensed oral 
      THU-decitabine for development as a treatment for sickle cell disease. EpiDestiny 
      did not fund this clinical trial, and had no role in the study design, collection 
      or analysis of the data, preparation of the manuscript, or the decision to 
      publish. None of the authors have received any payments related to conduct of 
      this clinical trial.
EDAT- 2017/09/08 06:00
MHDA- 2017/09/15 06:00
PMCR- 2017/09/07
CRDT- 2017/09/08 06:00
PHST- 2017/01/03 00:00 [received]
PHST- 2017/08/03 00:00 [accepted]
PHST- 2017/09/08 06:00 [entrez]
PHST- 2017/09/08 06:00 [pubmed]
PHST- 2017/09/15 06:00 [medline]
PHST- 2017/09/07 00:00 [pmc-release]
AID - PMEDICINE-D-17-00020 [pii]
AID - 10.1371/journal.pmed.1002382 [doi]
PST - epublish
SO  - PLoS Med. 2017 Sep 7;14(9):e1002382. doi: 10.1371/journal.pmed.1002382. 
      eCollection 2017 Sep.