Abstract

Two gene therapy products have been approved by the US Food and Drug Administration for sickle cell disease. Nearly all patients in the clinical trials that led to approval either were sickle hemoglobin (HbS) gene homozygotes (sickle cell anemia) or had HbS-β0 thalassemia. HbSC disease, caused by compound heterozygosity for HbS and hemoglobin C genes, is the second most common genotype of sickle cell disease. Gene therapy has not been tested in patients with HbSC disease who are severely symptomatic. We discuss the pathophysiology and clinical features of HbSC disease and how gene therapy is likely to provide a curative option for some individuals. We also discuss the mechanism through which fetal hemoglobin (HbF) and HbF-like HbA (HbAT87Q) might mitigate adverse clinical outcomes and end-organ damage in patients with HbSC disease and other compound heterozygous sickle hemoglobinopathies.

1.
Frangoul
H
,
Locatelli
F
,
Sharma
A
, et al
.
Exagamglogene autotemcel for severe sickle cell disease
.
N Engl J Med
.
2024
;
390
(
18
):
1649
-
1662
.
2.
Kanter
J
,
Walters
MC
,
Krishnamurti
L
, et al
.
Biologic and clinical efficacy of lentiglobin for sickle cell disease
.
N Engl J Med
.
2022
;
386
(
7
):
617
-
628
.
3.
Steinberg
MH
. Other sickle hemoglobinopathies. In:
Steinberg
MH
,
Forget
BG
,
Higgs
DR
,
Weatherall
DJ
, eds.
Disorders of hemoglobin: Genetics, Pathophysiology, and Clinical Management
. (10th ed) .
Cambridge University Press
;
2009
.
4.
Torres
LS
,
Okumura
JV
,
Belini-Júnior
É
, et al
.
Phenotypic diversity of sickle cell disease in patients with a double heterozygosity for Hb S and HbD-Punjab
.
Hemoglobin
.
2016
;
40
(
5
):
356
-
358
.
5.
Milner
PF
,
Miller
C
,
Grey
R
,
Seakins
M
,
DeJong
WW
,
Went
LN
.
Hemoglobin O Arab in four negro families and its interaction with hemoglobin S and hemoglobin C
.
N Engl J Med
.
1970
;
283
(
26
):
1417
-
1425
.
6.
Goode
E
,
Boruchov
D
,
Oliveira
JL
,
Lau
CC
.
Hemoglobin S/Hemoglobin Quebec-Chori presenting as sickle cell disease: a case report
.
J Pediatr Hematol Oncol
.
2020
;
42
(
8
):
e775
-
e777
.
7.
Venugopal
S
,
Shaju
A
,
Dhuri
S
,
Al-Harthy
T
,
Jabal
KB
.
Compound heterozygosity for Hb S and Hb S-Oman: case report
.
Sultan Qaboos Univ Med J
.
2008
;
8
(
3
):
344
-
346
.
8.
Luo
H
,
Adewoye
AH
,
Eung
SH
, et al
.
A novel sickle hemoglobin: hemoglobin S-South end
.
J Pediatr Hematol Oncol
.
2004
;
26
(
11
):
773
-
776
.
9.
Moo-Penn
W
,
Bechtel
K
,
Jue
D
, et al
.
The presence of hemoglobin S and C Harlem in an individual in the United States
.
Blood
.
1975
;
46
(
3
):
363
-
367
.
10.
Monplaisir
N
,
Merault
G
,
Poyart
C
, et al
.
Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes
.
Proc Natl Acad Sci U S A
.
1986
;
83
(
24
):
9363
-
9367
.
11.
Geva
A
,
Clark
JJ
,
Zhang
Y
,
Popowicz
A
,
Manning
JM
,
Neufeld
EJ
.
Hemoglobin Jamaica plain-a sickling hemoglobin with reduced oxygen affinity
.
N Engl J Med
.
2004
;
351
(
15
):
1532
-
1538
.
12.
Goosens
M
,
Garel
MC
,
Auvinet
J
, et al
.
Hemoglobin C Ziguinchor α2Aβ26 (A3) glu->val β58 (E2) pro->arg: the second sickling variant with amino acid substitutions in 2 residues of the β polypeptide chain
.
FEBS Let
.
1975
;
58
:
149
-
154
.
13.
Ducrocq
R
,
Dratkowski
P
,
Ithier
G
, et al
.
A new major sickle cell syndrome: HbS (β6Val)/HbC Ndjamena (β6Val-β37Gly)
.
Hemoglobin
.
2006
;
30
:
33
-
41
.
14.
Préhu
C
,
Riou
J
,
Sartelet
I
, et al
.
Hb O-Tibesti [beta121(GH4)Glu->Lys; beta11(A8)Val->Ile], a hemoglobin variant carrying in the same beta chain the substitutions of Hb O-Arab and Hb Hamilton, found in combination with Hb S [beta6(A3)Glu-->Val]
.
Hemoglobin
.
2002
;
26
(
1
):
13
-
20
.
15.
Paradisi
I
,
González
N
,
Hernández
A
,
Arias
S
.
Hemoglobin S/hemoglobin City of Hope compound heterozygote with a Sub Saharan genetic background and severe bone marrow hypoplasia
.
Invest Clin
.
2010
;
51
(
3
):
403
-
414
.
16.
Kutlar
F
,
Redding-Lallinger
R
,
Meiler
SE
,
Bakanay
SM
,
Borders
L
,
Kutlar
A
.
A new sickling variant 'Hb S-Wake β[(Glu6Val-Asn139 Ser)]' found in a compound heterozygote with Hb S β(Glu6Val) coinherited with homozygous α-thalassemia-2: phenotype and molecular characteristics
.
Acta Haematol
.
2010
;
124
(
2
):
120
-
124
.
17.
Masiello
D
,
Heeney
MM
,
Adewoye
AH
, et al
.
Hemoglobin SE disease: a concise review
.
Am J Hematol
.
2007
;
82
(
7
):
643
-
649
.
18.
Lawrence
C
,
Hirsch
RE
,
Fataliev
NA
,
Patel
S
,
Fabry
ME
,
Nagel
RL
.
Molecular interactions between Hb alpha-G Philadelphia, HbC, and HbS: phenotypic implications for SC alpha-G Philadelphia disease
.
Blood
.
1997
;
90
(
7
):
2819
-
2825
.
19.
Gu
L-H
,
Wilson
JB
,
Molchanova
TP
,
McKie
KM
,
McKie
VC
,
Huisman
TH
.
Three sickle cell anemia patients each with a different alpha chain variant. Diagnostic complications
.
Hemoglobin
.
1993
;
17
(
4
):
295
-
301
.
20.
Seward
DP
,
Ware
RE
,
Kinney
TR
.
Hemoglobin sickle-Lepore: report of two siblings and review of the literature
.
Am J Hematol
.
1993
;
44
(
3
):
192
-
195
.
21.
Ahmed
SG
,
Ibrahim
UA
.
Non-S sickling hemoglobin variants: historical genetic diagnostic and clinical perspectives
.
Oman Med J
.
2021
;
36
(
3
):
e261
.
22.
Minniti
C
,
Brugnara
C
,
Steinberg
MH
.
HbSC disease: a time for progress
.
Am J Hematol
.
2022
;
97
(
11
):
1390
-
1393
.
23.
Motulsky
AG
.
Frequency of sickle disorders in US blacks
.
N Engl J Med
.
1973
;
288
(
1
):
31
-
33
.
24.
Piel
FB
,
Howes
RE
,
Patil
AP
, et al
.
The distribution of haemoglobin C and its prevalence in newborns in Africa
.
Sci Rep
.
2013
;
3
:
1671
.
25.
Taylor
JG
,
Ackah
D
,
Cobb
C
, et al
.
Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease
.
Am J Hematol
.
2008
;
83
(
1
):
6
-
14
.
26.
Steinberg
MH
,
Nagel
RL
. HbSC disease and hemoglobin C disorders other sickle hemoglobinopathies. In:
Steinberg
MH
,
Forget
BG
,
Higgs
DR
,
Weatherall
DJ
, eds.
Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management
. (2nd ed) .
2009
.
27.
Platt
OS
,
Brambilla
DJ
,
Rosse
WF
, et al
.
Mortality in sickle-cell disease. Life expectancy and risk-factors for early death
.
N Engl J Med
.
1994
;
330
(
23
):
1639
-
1644
.
28.
Platt
OS
,
Thorington
BD
,
Brambilla
DJ
, et al
.
Pain in sickle cell disease. Rates and risk-factors
.
N Engl J Med
.
1991
;
325
(
1
):
11
-
16
.
29.
Lionnet
F
,
Hammoudi
N
,
Stojanovic
K
, et al
.
Hemoglobin sickle cell disease complications: a clinical study of 179 cases
.
Haematol
.
2012
;
97
(
8
):
1136
-
1141
.
30.
Brewin
JN
,
Nardo-Marino
A
,
Stuart-Smith
S
, et al
.
The pleiotropic effects of alpha thalassemia on HbSS and HbSC sickle cell disease: reduced erythrocyte cation co-transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival
.
Am J Hematol
.
2022
;
97
(
10
):
1275
-
1285
.
31.
Dei-Adomakoh
YA
,
Segbefia
CI
,
Latham
TS
, et al
.
Hydroxyurea for children and adults with hemoglobin SC disease
.
NEJM Evid
.
2025
;
4
(
2
):
EVIDoa2400402
.
32.
Steinberg
MH
,
Embury
SH
.
Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene
.
Blood
.
1986
;
68
(
5
):
985
-
990
.
33.
Shartava
A
,
Monteiro
CA
,
Bencsath
FA
, et al
.
A posttranslational modification of beta-actin contributes to the slow dissociation of the spectrin-protein 4.1-actin complex of irreversibly sickled cells
.
J Cell Biol
.
1995
;
128
(
5
):
805
-
818
.
34.
Goodman
SR
.
The irreversibly sickled cell: a perspective
.
Cell Mol Biol
.
2004
;
50
(
1
):
53
-
58
.
35.
Franco
RS
,
Puchulu-Campanella
ME
,
Barber
LA
, et al
.
Changes in the properties of normal human red blood cells during in vivo aging
.
Am J Hematol
.
2013
;
88
(
1
):
44
-
51
.
36.
Reese
TJ
,
Worth
EH
,
Fugate
MK
,
Levitt
MT
,
Ferrone
FA
.
Novel single-cell measurements suggest irreversibly sickled cells are neither dense nor dehydrated
.
Biophys J
.
2024
;
123
(
21
):
3750
-
3758
.
37.
Steinberg
MH
,
Nagel
RL
. HbSC disease and HbC disorders. In:
Steinberg
MH
,
Forget
BG
,
Higgs
DR
,
Weatherall
DJ
, eds.
Disorders of hemoglobin: Genetics, Pathophysiology, and Clinical Management
. (2nd ed) .
2009
.
38.
Nagel
RL
,
Fabry
ME
,
Steinberg
MH
.
The paradox of hemoglobin SC disease
.
Blood Rev
.
2003
;
17
(
3
):
167
-
178
.
39.
Eaton
WA
.
Impact of hemoglobin biophysical studies on molecular pathogenesis and drug therapy for sickle cell disease
.
Mol Aspects Med
.
2022
;
84
:
100971
.
40.
Hirsch
RE
,
Samuel
RE
,
Fataliev
NA
, et al
.
Differential pathways in oxy and deoxy HbC aggregation/crystallization
.
Proteins
.
2001
;
42
(
1
):
99
-
107
.
41.
Hirsch
RE
,
Raventos-Suarez
C
,
Olson
JA
,
Nagel
RL
.
Ligand state of intraerythrocytic circulating HbC crystals in homozygous CC patients
.
Blood
.
1985
;
66
(
4
):
775
-
777
.
42.
Hirsch
RE
,
Lin
MJ
,
Nagel
RL
.
The inhibition of hemoglobin C crystallization by hemoglobin F
.
J Biol Chem
.
1988
;
263
(
12
):
5936
-
5939
.
43.
Lin
MJ
,
Nagel
RL
,
Hirsch
RE
.
Acceleration of hemoglobin C crystallization by hemoglobin S
.
Blood
.
1989
;
74
(
5
):
1823
-
1825
.
44.
Gluckman
E
,
Cappelli
B
,
Bernaudin
F
, et al
.
Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation
.
Blood
.
2017
;
129
(
11
):
1548
-
1556
.
45.
Rostami
T
,
Rad
S
,
Rostami
MR
, et al
.
Hematopoietic stem cell transplantation in sickle cell disease: a multidimensional review
.
Cell Transpl
.
2024
;
33
:
9636897241246351
.
46.
Hsieh
MM
,
Kang
EM
,
Fitzhugh
CD
, et al
.
Allogeneic hematopoietic stem-cell transplantation for sickle cell disease
.
N Engl J Med
.
2009
;
361
(
24
):
2309
-
2317
.
47.
Shenoy
S
,
Eapen
M
,
Panepinto
JA
, et al
.
A trial of unrelated donor marrow transplantation for children with severe sickle cell disease
.
Blood
.
2016
;
128
(
21
):
2561
-
2567
.
48.
Kassim
AA
,
de la Fuente
J
,
Nur
E
, et al
.
An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease
.
Blood
.
2024
;
143
(
25
):
2654
-
2665
.
49.
Kassim
AA
,
Walters
MC
,
Eapen
M
, et al
.
Haploidentical bone marrow transplantation for sickle cell disease
.
NEJM Evid
.
2025
;
4
(
3
):
EVIDoa2400192
.
50.
Nakamae
H
.
Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation
.
Front Immunol
.
2024
;
15
:
1403936
.
51.
Miller
MK
,
Zimmerman
SA
,
Schultz
WH
,
Ware
RE
.
Hydroxyurea therapy for pediatric patients with hemoglobin SC disease
.
J Pediatr Hematol Oncol
.
2001
;
23
(
5
):
306
-
308
.
52.
Steinberg
MH
,
Nagel
RL
,
Brugnara
C
.
Cellular effects of hydroxyurea in Hb SC disease
.
Br J Haematol
.
1997
;
98
(
4
):
838
-
844
.
53.
Yates
AM
,
Dedeken
L
,
Smeltzer
MP
,
Lebensburger
JD
,
Wang
WC
,
Robitaille
N
.
Hydroxyurea treatment of children with hemoglobin SC disease
.
Pediatr Blood Cancer
.
2013
;
60
(
2
):
323
-
325
.
54.
Luchtman-Jones
L
,
Pressel
S
,
Hilliard
L
, et al
.
Effects of hydroxyurea treatment for patients with hemoglobin SC disease
.
Am J Hematol
.
2016
;
91
(
2
):
238
-
242
.
55.
Wang
W
,
Brugnara
C
,
Snyder
C
, et al
.
The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial
.
Br J Haematol
.
2011
;
152
(
6
):
771
-
776
.
56.
Powars
DR
,
Hiti
A
,
Ramicone
E
,
Johnson
C
,
Chan
L
.
Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors
.
Am J Hematol
.
2002
;
70
(
3
):
206
-
215
.
57.
Setayesh
T
,
Chi
M
,
Oestreicher
Z
, et al
.
A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea
.
Blood
.
2025
;
146
(
1
):
13
-
28
.
58.
Porcu
S
,
Simbula
M
,
Marongiu
MF
, et al
.
Delta-globin gene expression improves sickle cell disease in a humanised mouse model
.
Br J Haematol
.
2021
;
193
(
6
):
1228
-
1237
.
59.
Eaton
WA
,
Bunn
HF
.
Treating sickle cell disease by targeting HbS polymerization
.
Blood
.
2017
;
129
(
20
):
2719
-
2726
.
60.
Yang
E
,
Voelkel
EB
,
Lezon-Geyda
K
,
Schulz
VP
,
Gallagher
PG
.
Hemoglobin C trait accentuates erythrocyte dehydration in hereditary xerocytosis
.
Pediatr Blood Cancer
.
2017
;
64
(
8
):
e26444
.
61.
Gallagher
PG
.
Disorders of erythrocyte hydration
.
Blood
.
2017
;
130
(
25
):
2699
-
2708
.
62.
Hinchliffe
RF
,
Norcliffe
D
,
Farrar
LM
,
Lilleyman
JS
.
Mean cell haemoglobin concentration in subjects with haemoglobin C, D, E and S traits
.
Clin Lab Haematol
.
1996
;
18
(
4
):
245
-
248
.
63.
Bunn
HF
.
Subunit dissociation of certain abnormal human hemoglobins
.
J Clin Invest
.
1969
;
48
(
1
):
126
-
138
.
64.
Park
CM
.
The dimerization of deoxyhemoglobin and of oxyhemoglobin. Evidence for cleavage along the same plane
.
J Biol Chem
.
1970
;
245
(
20
):
5390
-
5394
.
65.
Bunn
HF
,
McDonough
M
.
Asymmetrical hemoglobin hybrids. An approach to the study of subunit interactions
.
Biochemistry
.
1974
;
13
(
5
):
988
-
993
.
66.
Gupta
AO
,
Sharma
A
,
Dalal
J
, et al
. Base editing for sickle cell disease: ongoing results from the BEACON study evaluating the safety and efficacy of BEAM-101, the first base-edited autologous CD34+ HSPC one-time cell therapy. Paper presented at: European Hematology Association (EHA) 2025 Congress.
13 June 2025
. Milan, Italy.
67.
Steinberg
MH
.
Fetal hemoglobin in beta hemoglobinopathies: is enough too much?
.
Am J Hematol
.
2022
;
97
(
6
):
676
-
678
.
68.
Li
C
,
Georgakopoulou
A
,
Newby
GA
, et al
.
In vivo HSC prime editing rescues sickle cell disease in a mouse model
.
Blood
.
2023
;
141
(
17
):
2085
-
2099
.
69.
Breda
L
,
Papp
TE
,
Triebwasser
MP
, et al
.
In vivo hematopoietic stem cell modification by mRNA delivery
.
Science
.
2023
;
381
(
6656
):
436
-
443
.
70.
Frangoul
H
,
Stults
A
,
Bruce
K
, et al
.
Best practices in gene therapy for sickle cell disease and transfusion-dependent β-thalassemia
.
Transpl Cell Ther
.
2025
;
31
(
6
):
352.e1
-
352.e10
.
71.
Fitzhugh
CD
,
Hsieh
MM
,
Bolan
CD
,
Saenz
C
,
Tisdale
JF
.
Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium?
.
Cytotherapy
.
2009
;
11
(
4
):
464
-
471
.
72.
Steinberg
MH
.
Fetal hemoglobin in sickle hemoglobinopathies: high HbF genotypes and phenotypes
.
J Clin Med
.
2020
;
9
(
11
):
3782
.
73.
Steinberg
MH
,
Kutlar
A
,
Sebastiani
P
,
Sebastiani
P
.
Mean corpuscular hemoglobin modulates HbF/F-cell and clinical response to gene therapy and hydroxyurea in sickle cell disease
.
Am J Hematol
.
2025
;
100
(
9
):
1647
-
1650
.
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