RT Book, Section
A1 Kutlar, Abdullah
A1 A. Sheehan, Vivien
A2 Gladwin, Mark T.
A2 Kato, Gregory J.
A2 Novelli, Enrico M.
SR Print(0)
ID 1179338538
T1 Pharmacologic Induction of Fetal Hemoglobin
T2 Sickle Cell Disease
YR 2021
FD 2021
PB McGraw-Hill Education
PP New York, NY
SN 9781260458596
LK hemonc.mhmedical.com/content.aspx?aid=1179338538
RD 2024/09/14
AB The  presence  of  fetal  hemoglobin  (HbF,α2γ2)  is  known  to  reduce  the  clinical  complications  of  sickle  cell  disease  (SCD).  Pharmacologic  agents  able  to  induce  HbF  have  been  sought  after  for  decades.  Agnostic  drug  screens  have  been  unsuccessful,  and  progress  in  identifying  novel  HbF-inducing  agents  was  slowed  by  our  limited  understanding  of  γ-globin  regulation.  Our  understanding  of  γ-globin  induction  was  increased  significantly  by  an  unbiased  genome-wide  association  study  (GWAS)  approach,  which  identified  variants  in  the  transcription  factor  B-cell  lymphoma/leukemia  11A  (BCL11A)  and  regulatory  elements  within  the  intergenic  region  HBS1L-MYB  as  associated  with  HbF  levels.  Functional  studies  subsequently  established  the  roles  of  BCL11A,  MYB,  and  KLF1  in  γ-globin  repression,  and  disruption  of  the  BCL11A  erythroid  enhancer  element  is  now  a  gene  therapy  target  in  >1  clinical  trial.  Gene  therapy  may  provide  a  cure  for  SCD,  either  through  HbF  induction  or  correction  of  the  causative  mutation,  but  several  technical  and  safety  hurdles  must  be  overcome  before  this  therapy  can  be  offered  widely,  particularly  in  low-resource  countries,  where  99%  of  individuals  with  SCD  reside.  Pharmacologic  therapies  to  treat  SCD  are  still  needed,  and  hydroxyurea,  developed  for  use  in  SCD  almost  3  decades  ago,  remains  the  only  widely  used  pharmacologic  HbF  inducer.