Abstract
Pyruvate kinase (PK) is a key enzyme in glycolysis, the sole source of adenosine triphosphate, which is essential for all energy-dependent activities of red blood cells. Activating PK shows great potential for treating a broad range of hemolytic anemias beyond PK deficiency, because they also enhance activity of wild-type PK. Motivated by observations of sickle-cell complications in sickle-trait individuals with concomitant PK deficiency, activating endogenous PK offers a novel and promising approach for treating patients with sickle-cell disease.
References
1.
Betz
T
, Lenz
M
, Joanny
JF
, Sykes
C
. ATP-dependent mechanics of red blood cells
. Proc Natl Acad Sci U S A
. 2009
;106
(36
):15320
-15325
.2.
McMahon
TJ
, Darrow
CC
, Hoehn
BA
, Zhu
H
. Generation and export of red blood cell ATP in health and disease
. Front Physiol
. 2021
;12
:754638
.3.
Brown
KA
. Erythrocytes metabolism and enzyme defects
. Lab Med
. 1996
;27
(5
):329
-333
.4.
Poillon
WN
, Kim
BC
. 2,3-diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S
. Blood
. 1990
;76
(5
):1028
-1036
.5.
Poillon
WN
, Kim
BC
, Labotka
RJ
, Hicks
CU
, Kark
JA
. Antisickling effects of 2,3-diphosphoglycerate depletion
. Blood
. 1995
;85
(11
):3289
-3296
.6.
Eaton
WA
, Bunn
HF
. Treating sickle cell disease by targeting HbS polymerization
. Blood
. 2017
;129
(20
):2719
-2726
.7.
Grace
RF
, Bianchi
P
, van Beers
EJ
, et al. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study
. Blood
. 2018
;131
(20
):2183
-2192
.8.
Zanella
A
, Fermo
E
, Bianchi
P
, Valentini
G
. Red cell pyruvate kinase deficiency: molecular and clinical aspects
. Br J Haematol
. 2005
;130
(1
):11
-25
.9.
Vander Heiden
MG
. Targeting cancer metabolism: a therapeutic window opens
. Nat Rev Drug Discov
. 2011
;10
(9
):671
-684
.10.
Zahra
K
, Dey
T
, Ashish
, Mishra
SP
, Pandey
U
. Pyruvate kinase M2 and cancer: the role of PKM2 in promoting tumorigenesis
. Front Oncol
. 2020
;10
:159
.11.
Kung
C
, Hixon
J
, Kosinski
PA
, et al. AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency
. Blood
. 2017
;130
(11
):1347
-1356
.12.
Al-Samkari
H
, Galacteros
F
, Glenthoj
A
, et al. Mitapivat versus placebo for pyruvate kinase deficiency
. N Engl J Med
. 2022
;386
(15
):1432
-1442
.13.
Glenthoj
A
, van Beers
EJ
, Al-Samkari
H
, et al. Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial
. Lancet Haematol
. 2022
;9
(10
):e724
-e732
.14.
Yang
H
, Merica
E
, Chen
Y
, et al. Phase 1 single- and multiple-ascending-dose randomized studies of the safety, pharmacokinetics, and pharmacodynamics of AG-348, a first-in-class allosteric activator of pyruvate kinase R, in healthy volunteers
. Clin Pharmacol Drug Dev
. 2019
;8
(2
):246
-259
.15.
Matte
A
, Federti
E
, Kung
C
, et al. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a beta-thalassemia mouse model
. J Clin Invest
. 2021
;131
(10
):e144206
.16.
Kuo
KHM
, Layton
DM
, Lal
A
, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent alpha-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase 2 study
. Lancet
. 2022
;400
(10351
):493
-501
.17.
Gladwin
MT KG
, Novelli
EM
. Sickle Cell Disease. McGraw Hill/Medical
; 2021
.18.
Charache
S
, Grisolia
S
, Fiedler
AJ
, Hellegers
AE
. Effect of 2,3-diphosphoglycerate on oxygen affinity of blood in sickle cell anemia
. J Clin Invest
. 1970
;49
(4
):806
-812
.19.
Cohen-Solal
M
, Prehu
C
, Wajcman
H
, et al. A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an alpha2 globin gene variant (Hb Conakry)
. Br J Haematol
. 1998
;103
(4
):950
-956
.20.
Alli
N
, Coetzee
M
, Louw
V
, et al. Sickle cell disease in a carrier with pyruvate kinase deficiency
. Hematology
. 2008
;13
(6
):369
-372
.21.
Xu
JZ
, Thein
SL
. The carrier state for sickle cell disease is not completely harmless
. Haematologica
. 2019
;104
(6
):1106
-1111
.22.
Wang
X
, Gardner
K
, Tegegn
MB
, et al. Genetic variants of PKLR are associated with acute pain in sickle cell disease
. Blood Adv
. 2022
;6
(11
):3535
-3540
.23.
Wang
X
, Fu
YP
, Li
Q
, et al. Pklr variants associated with acute pain in sickle cell disease influence ATP concentrations in red blood cells
. Blood
. 2022
;140
:954
-956
.24.
Rab
MAE
, Bos
J
, van Oirschot
BA
, et al. Decreased activity and stability of pyruvate kinase in sickle cell disease: a novel target for mitapivat therapy
. Blood
. 2021
;137
(21
):2997
-3001
.25.
Shrestha
A
, Chi
M
, Wagner
K
, et al. FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice
. Blood Adv
. 2021
;5
(9
):2385
-2390
.26.
Quezado
ZMN
, Kamimura
S
, Smith
M
, et al. Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model
. Blood Cells Mol Dis
. 2022
;95
:102660
.27.
Xu
JZ
, Conrey
A
, Frey
I
, et al. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease
. Blood
. 2022
;140
(19
):2053
-2062
.28.
van Dijk
MJ
, Rab
MAE
, van Oirschot
BA
, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: a phase 2, open-label study
. Am J Hematol
. 2022
;97
(7
):E226
-E229
.29.
Brown
RC
, K; Kalfa
TA
, Kuypers
FA
, et al. FT-4202, an allosteric activator of pyruvate kinase-R, demonstrates proof of mechanism and proof of concept after a single dose and after multiple daily doses in a phase 1 study of patients with sickle cell disease
. Blood
. 2020
;136
:19
-20
.30.
Schroeder
P
, Fulzele
K
, Forsyth
S
, et al. Etavopivat, a pyruvate kinase activator in red blood cells, for the treatment of sickle cell disease
. J Pharmacol Exp Ther
. 2022
;380
(3
):210
-219
.31.
Forsyth
S
, Schroeder
P
, Geib
J
, et al. Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial
. Clin Pharmacol Drug Dev
. 2022
;11
(5
):654
-665
.32.
Bunn
HF
. Oxygen delivery in the treatment of anemia
. N Engl J Med
. 2022
;387
(25
):2362
-2365
.33.
Sunshine
HR
, Hofrichter
J
, Ferrone
FA
, Eaton
WA
. Oxygen binding by sickle cell hemoglobin polymers
. J Mol Biol
. 1982
;158
(2
):251
-273
.34.
Henry
ER
, Harper
J
, Glass
KE
, Metaferia
B
, Louis
JM
, Eaton
WA
. MWC allosteric model explains unusual hemoglobin-oxygen binding curves from sickle cell drug binding
. Biophys J
. 2021
;120
(12
):2543
-2551
.35.
Henry
ER
, Metaferia
B
, Li
Q
, et al. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin
. Blood
. 2021
;138
(13
):1172
-1181
.36.
Howard
J
, Ataga
KI
, Brown
RC
, et al. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial
. Lancet Haematol
. 2021
;8
(5
):e323
-e333
.37.
Inusa
BPD
, Casale
M
, Campbell
A
, Archer
N
. Will the changing therapeutic landscape meet the needs of patients with sickle cell disease?
. Lancet Haematol
. 2021
;8
(5
):e306
-e307
.38.
Konté
K
, Baas
KPA
, Afzali-Hashemi
L
, et al. Effect of voxelotor on cerebral perfusion and cerebral oxygen metabolism in adult patients with sickle cell disease; preliminary results of the Coverage Study
. Blood
. 2022
;140
:2535
-2536
.39.
Duhm
J
. Effects of 2,3-diphosphoglycerate and other organic phosphate compounds on oxygen affinity and intracellular pH of human erythrocytes
. Pflügers Arch
. 1971
;326
(4
):341
-356
.40.
Hofrichter
J
, Ross
PD
, Eaton
WA
. Supersaturation in sickle cell hemoglobin solutions
. Proc Natl Acad Sci U S A
. 1976
;73
(9
):3035
-3039
.41.
Goldberg
MA
, Husson
MA
, Bunn
HF
. Participation of hemoglobins A and F in polymerization of sickle hemoglobin
. J Biol Chem
. 1977
;252
(10
):3414
-3421
.42.
Briehl
RW
. Gelation of sickle cell hemoglobin. IV. Phase transitions in hemoglobin S gels: separate measures of aggregation and solution--gel equilibrium
. J Mol Biol
. 1978
;123
(4
):521
-538
.43.
Henry
ER
, Mozzarelli
A
, Viappiani
C
, et al. Experiments on hemoglobin in single crystals and silica gels distinguish among allosteric models
. Biophys J
. 2015
;109
(6
):1264
-1272
.44.
Bunn
HF
. Pathogenesis and treatment of sickle cell disease
. N Engl J Med
. 1997
;337
(11
):762
-769
.45.
Eaton
WA
, Hofrichter
J
. Hemoglobin S gelation and sickle cell disease
. Blood
. 1987
;70
(5
):1245
-1266
.46.
Li
Q
, Henry
ER
, Hofrichter
J
, et al. Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease
. Proc Natl Acad Sci U S A
. 2017
;114
(5
):E689
-E696
.47.
Park
Y
, Best
CA
, Auth
T
, et al. Metabolic remodeling of the human red blood cell membrane
. Proc Natl Acad Sci U S A
. 2010
;107
(4
):1289
-1294
.48.
Jensen
M
, Shohet
SB
, Nathan
DG
. The role of red cell energy metabolism in the generation of irreversibly sickled cells in vitro
. Blood
. 1973
;42
(6
):835
-842
.49.
El Nemer
W
, Godard
A
, El Hoss
S
. Ineffective erythropoiesis in sickle cell disease: new insights and future implications
. Curr Opin Hematol
. 2021
;28
(3
):171
-176
.50.
Bennett
V
, Stenbuck
PJ
. The membrane attachment protein for spectrin is associated with band 3 in human erythrocyte membranes
. Nature
. 1979
;280
(5722
):468
-473
.51.
Ferru
E
, Giger
K
, Pantaleo
A
, et al. Regulation of membrane-cytoskeletal interactions by tyrosine phosphorylation of erythrocyte band 3
. Blood
. 2011
;117
(22
):5998
-6006
.52.
Mohandas
N
, Gallagher
PG
. Red cell membrane: past, present, and future
. Blood
. 2008
;112
(10
):3939
-3948
.53.
Lux
SEt
. Anatomy of the red cell membrane skeleton: unanswered questions
. Blood
. 2016
;127
(2
):187
-199
.54.
Noomuna
P
, Risinger
M
, Zhou
S
, et al. Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease
. Br J Haematol
. 2020
;190
(4
):599
-609
.55.
Terra
HT
, Saad
MJ
, Carvalho
CR
, Vicentin
DL
, Costa
FF
, Saad
ST
. Increased tyrosine phosphorylation of band 3 in hemoglobinopathies
. Am J Hematol
. 1998
;58
(3
):224
-230
.56.
Le
K
, Wang
X
, Lundt
M
, et al. Activating pyruvate kinase improves red blood cell integrity by reducing Band3 tyrosine phosphorylation
. Blood
. 2022
;140
:5395
-5396
.57.
Lundt
M
, Asomaning
N
, Frey
I
, et al. The pyruvate kinase activator mitapivat improves red blood cell deformability and sickling kinetics in adult patients with sickle cell disease
. Blood
. 2022
;140
:2508
-2509
.58.
Little
JA
. RBC, heal thyself: PK activators in SCD
. Blood
. 2022
;140
(19
):2005
-2006
.59.
Grace
RF
, Rose
C
, Layton
DM
, et al. Safety and efficacy of mitapivat in pyruvate kinase deficiency
. N Engl J Med
. 2019
;381
(10
):933
-944
.60.
Collaborators GBDSCD
. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021
. Lancet Haematol
. 2023
;10
(8
):e585
-e599
.61.
Migotsky
M
, Beestrum
M
, Badawy
SM
. Recent advances in sickle-cell disease therapies: a review of voxelotor, crizanlizumab, and L-glutamine
. Pharmacy (Basel)
. 2022
;10
(5
):10050123
.62.
Salinas Cisneros
G
, Thein
SL
. Recent advances in the treatment of sickle cell disease
. Front Physiol
. 2020
;11
:435
.63.
Telen
MJ
. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease
. Blood
. 2016
;127
(7
):810
-819
.64.
Thornburg
CD
, Calatroni
A
, Telen
M
, Kemper
AR
. Adherence to hydroxyurea therapy in children with sickle cell anemia
. J Pediatr
. 2010
;156
(3
):415
-419
.65.
Cronin
RM
, Lin
CJ
, Chiang
C
, MacEwan
SR
, DeBaun
MR
, Hyer
JM
. The use of FDA-approved medications for preventing vaso-occlusive events in sickle cell disease
. Blood Adv
. 2023
;7
(13
):3114
-3116
.66.
Tisdale
JF
, Thein
SL
, Eaton
WA
. Treating sickle cell anemia
. Science
. 2020
;367
(6483
):1198
-1199
.67.
Menzel
S
, Garner
C
, Gut
I
, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15
. Nat Genet
. 2007
;39
(10
):1197
-1199
.68.
Tanhehco
YC
, Nathu
G
, Vasovic
LV
. Development of curative therapies for sickle cell disease
. Front Med (Lausanne)
. 2022
;9
:1055540
.69.
Metaferia
B
, Cellmer
T
, Dunkelberger
EB
, et al. Phenotypic screening of the ReFRAME drug repurposing library to discover new drugs for treating sickle cell disease
. Proc Natl Acad Sci U S A
. 2022
;119
(40
):e2210779119
.2024
You do not currently have access to this content.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal