REVIEW

Advances in the Treatment of Sickle Cell

Disease
Sargam Kapoor, MD; Jane A. Little, MD; and Lydia H. Pecker, MD

Abstract

Sickle cell disease (SCD) is a monogenic disorder that afflicts approximately 100,000 Americans and
millions of people worldwide. It is characterized by hemolytic anemia, vaso-occlusive crises, relentless
end-organ injury, and premature death. Currently, red blood cell transfusion and hydroxyurea are the
major disease-modifying therapies available for SCD. Hematopoetic stem cell transplant is curative, but
barriers to treatment are substantial and include a lack of suitable donors, immunologic transplant
rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, which is
especially problematic for older patients. Gene therapy to correct the bs point mutation is under inves-
tigation as another curative modality. Deeper insights into the pathophysiology of SCD have led to the
development of novel agents that target cellular adhesion, inflammation, oxidant injury, platelets and/or
coagulation, vascular tone, and hemoglobin polymerization. These agents are in preclinical and clinical
trials. One such agent, L-glutamine, decreases red blood cell oxidant injury and is recently US Food and
Drug Administration approved to prevent acute pain episodes of SCD in patients 5 years of age or older.
The purpose of this review is to describe the currently established therapies, barriers to curative therapies,
and novel therapeutic agents that can target sickle cell hemoglobin polymerization and/or its downstream
sequelae. A PubMed search was conducted for articles published up to May 15, 2018, using the search
terms sickle cell disease, novel treatments, hematopoietic stem cell transplantation, and gene therapy. Studies
cited include case series, retrospective studies, prospective clinical trials, meta-analyses, online abstracts,
and original reviews.
ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2018;nn(n):1-15

From the Division of He-

F
or this review, we conducted a PubMed
search for articles published up to May
15, 2018, using the search terms sickle
cell disease, novel treatments, hematopoietic stem
cell transplantation, and gene therapy. Studies
cited include case series, retrospective studies,
prospective clinical trials, meta-analyses, online
abstracts, and original reviews.
Sickle cell disease (SCD), described as the
“first molecular disease” in 1949,1 comprises
congenital hemolytic anemias caused by the
inheritance of point mutations in the b-globin
allele. Sickle cell disease is an umbrella term
that includes homozygous sickle cell anemia
(SCA), which is defined by the exclusive pro-
duction of hemoglobin [Hb] S (HbSS and
HbSb0), and compound heterozygous SCD,
defined by the production of HbS and another
abnormal b-globin protein (HbS/bþ thalas-
semia, HbSC, or HbS inherited with other
Hb variants like HbD, HbE, Hb Lepore, Hb
O Arab), also called sickle cell variant disease.
Life expectancy is shortest for people with
matology/ Oncology,
HbSS and HbSb0 who are at greater risk for Department of Medicine,
central nervous system complications, ne- University Hospitals
phropathy, and early death than people with Cleveland Medical Center,
Cleveland, OH (S.K.,
compound heterozygous SCD.2,3 Across geno- J.A.L.); Division of Hema-
types, clinical phenotype is improved by the tology/Oncology, Case
presence of high HbF levels and/or coinheri- Western Reserve Univer-
sity, Cleveland, OH (S.K.,
tance of the a-thalassemia trait.4,5 J.A.L.); and Division of Pe-
diatric Hematology, Johns
PATHOPHYSIOLOGY Hopkins University School
of Medicine, Baltimore,
Multiple pathophysiologic mechanisms MD (L.H.P.).
contribute to the clinical manifestations of
SCD. Under conditions of low oxygen tension,
HbS polymerizes in red blood cells (RBCs) and
forms elongated rods that alter RBC rheology.
Hemoglobin S polymerization is initially
reversible, but repeated deoxygenation/reoxy-
genation cycles cause RBC surface property
changes, membrane damage, and hemolysis.
Altered RBC conformation leads to vaso-
occlusion, ischemia, and inflammation.6-9
Hemoglobin Secontaining reticulocytes are

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ARTICLE HIGHLIGHTS
d Historically, long-term treatment with red blood cell trans-
fusions and hydroxyurea have been the only disease-modifying
therapies to treat sickle cell disease. L-glutamine, a precursor
of the antioxidant nicotinamide adenine dinucleotide phosphate,
was recently approved by the US Food and Drug Adminitration
to prevent acute pain episodes of sickle cell disease (SCD) in
patients 5 years of age or older; many other drugs are under
investigation.
d Two curative therapies for SCD are being studied: hemato-
poietic stem cell transplant and gene therapy. Hematopoietic
stem cell transplant cures some patients with SCD, and obsta-
cles to widespread use include the lack of suitable donors,
concern for immunologic transplant rejection, and long-term
adverse effects (especially for older patients). Gene therapy to
correct the bs mutation is under investigation. Both of these
strategies require further study.
d Sickle cell disease’s complex pathophysiology includes patho-
logic interactions of sickled red blood cells, reticulocytes, neu-
trophils, platelets, adhesion molecules, and the vascular
endothelium. This forms the basis for novel agents, currently
under development, targeting cellular adhesion, inflammation,
oxidative injury, vascular tone, and hemoglobin polymerization.
more adherent and may trap older misshapen
RBCs in postcapillary venules, where oxygen
tension is lower.10 Pathologic interactions be-
tween the vascular endothelium, leukocytes,
and platelets also contribute to SCD pathol-
ogy.6,11 Increased endothelial E- and P-selec-
tin activity,8 RBC intercellular adhesion
molecule 4 and basal cell adhesion molecule/
Lutheran activity,8,12,13 leukocyte adhesion,14
platelet activation,15-19 and nitric oxide (NO)
depletion20-22 contribute to acute and chronic
vascular injury and pain (Figure 1). Ongoing
drug development efforts target these
mechanisms.
EPIDEMIOLOGY AND CLINICAL
COMPLICATIONS
In the United States, 90,000 to 100,000 people
have SCD,23 and survival into adulthood is
nearly universal.24 Improved survival is a conse-
quence of 6 decades of progress in the field.
Common diagnostic, prevention, and treatment
n n
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MAYO CLINIC PROCEEDINGS
strategies responsible for these advances include
newborn screening, penicillin prophylaxis,25
vaccinations against encapsulated organisms,
transcranial Doppler (TCD) screening (to iden-
tify and then treat children at risk of stroke
with transfusions),26,27 and aggressive, inten-
sive hospital-based care. For patients with
HbSS and HbSb0, early initiation of hydroxy-
urea has also contributed to decreased symptom
burden and is associated with increased
longevity.28 In resource-rich countries, the
burden of morbidity and mortality from chronic
end-organ damage has shifted into adulthood.
Globally, nearly two-thirds of infants with
HbSS are born in Nigeria, the Republic of
Congo, or India, where childhood mortality
remains high.29 By 2050, the increased use
of newborn screening and penicillin prophy-
laxis and vaccination in developing countries
may prevent up to 5 million deaths in children
with SCD.29 In 2010, the number of newborns
with homozygous SCD worldwide was
305,800. By 2050, it will be approximately
400,000.29 This expanding and aging popula-
tion of people with SCD is likely to place
major demands on global health care
resources if they experience the protean clin-
ical manifestations of SCD.
Sickle cell disease complications are acute
and chronic. Acute complications include
pain crises, acute chest syndrome, stroke,
and hepatic or splenic sequestration. Common
sites of chronic injury are the brain, eyes,
heart, kidneys, lungs, and liver. These compli-
cations require intensive outpatient, inpatient,
and emergency department care. Unfortu-
nately, despite considerable need, few curative
therapies or disease-modifying agents that
target the underlying pathobiology in SCD
exist.
Hydroxyurea and long-term treatment
with blood transfusions are the only disease
modifying therapies that prevent and treat
acute and chronic complications in SCD. Allo-
geneic hematopoietic stem cell transplant
(HSCT) is the only cure, and gene therapy is
under investigation as a potential curative
strategy. Further advances in our understand-
ing of the underlying pathophysiology of SCD
contribute to the development of exciting and
novel targeted therapies to prevent and treat
SCD complications. Drugs that inhibit cellular
adhesion, reduce oxidative injury, membrane
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NOVEL TREATMENTS FOR SICKLE CELL DISEASE

FIGURE 1. Pathophysiology of vaso-occlusion in sickle cell disease. Hemolysis of sickle red blood cells (RBCs) releases heme that
depletes nitric oxide (NO) and causes monocyte activation, thereby triggering endothelial activation. Increased activity of endothelial
E-selectin and P-selectin results in leukocyte adhesion. In addition, increased erythrocyte intercellular adhesion molecule (ICAM) 4
expression binds endothelial aVb3 integrin, and leukocyte-expressed activated aMb2 integrin (MAC-1) traps hemoglobin Se
containing RBCs, leading to adhesion and consequent vaso-occlusion. Antiadhesive therapies (yellow) may decrease adhesion as
shown. ESL 1 ¼ E-selectin ligand 1; IL 1b ¼ interleukin 1b; IVIG ¼ intravenous immunoglobulin; PSGL 1 ¼ P-selectin glycoprotein
ligand; TNF a ¼ tumor necrosis factor a; VCAM ¼ vascular cell adhesion molecule. Adapted with permission of the American Society
of Hematology from Blood,6 with permission conveyed through the Copyright Clearance Center, Inc.

damage, and hemolysis, or increase NO myeloproliferative diseases. Hydroxyurea

bioavailability are in clinical trials,30 as are
novel gene-editing strategies that incorporate
autologous stem cell modification and
transplant.
In this review, we discuss established and
developing treatments for SCD (Table) and clas-
sify them on the basis of their mechanism of
action (Figure 2). Therapies that decrease HbS
polymerization are discussed first, followed by
those that target the downstream effects of
HbS polymerization.
REDUCTION OF HBS POLYMER FORMATION
AND CORRECTING THE MOLECULAR
DEFECT
Hydroxyurea
Hydroxyurea was the first US Food and Drug
Administration (FDA)eapproved drug for the
treatment of homozygous SCD and is the only
disease-modifying therapy that is supported by
robust evidence in children and adults. Hydroxy-
urea is a ribonucleoside diphosphate reductase
inhibitor first used as cytoreductive therapy for
increases fetal Hb (HbF; a2g2) production and
decreases intracellular HbS polymerization, an
effect that is sustained with long-term use but is
reversible on drug discontinuation.31 The dis-
covery that hydroxyurea increases HbF levels
led to initial trials of the drug in patients with
HbSS.32,33 Secondary cellular benefits from
hydroxyurea for patients with homozygous
SCD include decreasing leukocyte, platelet, and
reticulocyte counts and changes in cellular, in-
flammatory, and adhesion molecule expression
that reduce pathologic cellular adhesion and
inflammation.34-36
Studies in adults and children supporting
the use of hydroxyurea in homozygous SCD
led to the FDA’s approval of hydroxyurea for
adults nearly 20 years ago and for children
in 2017. The 1995 Multicenter Study of
Hydroxyurea (MSH) was a randomized,
placebo-controlled trial of hydroxyurea in
adults with HbSS. In the MSH, those treated
with hydroxyurea had fewer painful crises
and acute chest syndromes (2.5 vs 4.5 crises
per year and 25 vs 51, respectively; P<.001),

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 MAYO CLINIC PROCEEDINGS

TABLE. Ongoing or Completed Drug Trials for Sickle Cell Disease

Target Study drug Mechanism of action ClinicalTrials. gov Identifier Status (phase)
Oxidative injury Glutamine Increases NADPH NCT01179217 Completed (3)
NAC Increases glutathione NCT01849016 Completed (3)
Omega-3 FA Antioxidant NCT02947100 Ongoing (1, 2)
NCT02604368 Ongoing (3)
á-Lipoic acid Increases glutathione NCT01054768 Completed (2)
Acetyl-L-carnitine Decreases lipid peroxidation
Omega-3
Curcumin
Gum arabic
Adhesion Crizanlizumab Monoclonal antibody against P-selectin NCT01895361 Completed (2)
Rivapansel Pan-selectin inhibition NCT02187003 Ongoing (3)
IVIG Inhibits leukocyte activation/adhesion NCT01757418 Ongoing (1, 2)
Heparin Inhibitor of P-selectin NCT02098993 Ongoing (2)
Propranolol Inhibits RBC adhesion to endothelium NCT02012777 Terminated (1)
NCT01077921 Completed (2)
Hemoglobin F induction Decitabine Demethylation/ activation of ã-globin gene NCT01685515 Ongoing (1)
Pomalidomide Histone deacetylase inhibition NCT01522547 Completed (1)
Dimethylbutyrate Histone deacetylase inhibition NCT01322269 Completed (2)
Other antisickling agents Aes-103 Shifts Oxy-Hb NCT01597401 Completed (1)
GBT440 dissociation curve to left NCT03036813 Ongoing (3)
INCB059872 Hypomethylating agent, increases HbF NCT03132324 Ongoing (1)
Panobinostat Histone deacetylase inhibitor, increases HbF NCT01245179 Ongoing (1)
Senicapoc Inhibits cell dehydration NCT00040677 Completed (2)
NCT00102791 Terminated (3)
Sanguinate Carbon monoxide releasing/oxygen transfer agent NCT02411708 Ongoing (2)
SCD-101 Antisickling agent, unknown mechanism NCT02380079 Ongoing (1b)
Antiplatelet therapy Prasugrel Inhibition of platelet activation (ADP receptor blockade) NCT01794000 Terminated (3)
Ticagrelor NCT02482298 Completed (2)
Eptifibatide NCT00834899 Terminated (1, 2)
Anti-inflammatory agents Simvastatin Activates endothelial NO synthase NCT01702246 Completed (1)
Zileuton Inhibition of leukotrienes NCT01136941 Completed (1)
Regadenoson Agonist of adenosine receptor NCT01788631 Ongoing (2)
Vascular tone Magnesium Improves vascular tone NCT01197417 Completed (2, 3)
L-arginine Substrate for NO NCT02447874 Ongoing (1, 2)
Anticoagulant mechanism Rivaroxaban Inhibition of coagulation cascade NCT02072668 Ongoing (2)
Apixaban (exact mechanism being studied) NCT02179177 Ongoing (2)
ADP ¼ adenosine diphosphate; HbF ¼ hemoglobin F; IVIG ¼ intravenous immunoglobulin; NAC ¼ N-acetylcysteine; NADPH ¼ reduced nicotinamide adenine dinu-
cleotide phosphate; NO ¼ nitric oxide; omega 3-FA ¼ omega-3 fatty acid; Oxy-Hb ¼ oxyhemoglobin; RBC ¼ red blood cell.

required fewer blood transfusions (used in 48
vs 73 patients; P¼.001), and experienced less
overall long-term mortality (40% reduction;
P¼.04) compared with control patients who
received placebo.37,38 Based on the results of
the MSH, the FDA approved hydroxyurea for
adults with HbSS disease.
n n
4 Mayo Clin Proc.
The Pediatric Hydroxyurea Phase III Clin-
ical Trial (BABY HUG) was a phase 3 multicenter
placebo-controlled trial of hydroxyurea for in-
fants (9-18 months) with HbSS. BABY HUG
did not meet its primary end points: there was
no difference in splenic or renal function in chil-
dren treated with placebo vs hydroxyurea.28
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NOVEL TREATMENTS FOR SICKLE CELL DISEASE
However, hydroxyurea significantly decreased
painful crises, dactylitis, and the frequency and
duration of hospitalization, without resulting
in significant toxicity.31,39-42
Previously, data for children older than 18
months had been limited to observational
studies that supported the long-term use of hy-
droxyurea in this age group.43 However, recent
observational and randomized data have
emerged that strongly encourage the use of hy-
droxyurea in children.44-47 According to the
2014 National Heart, Lung, and Blood Institute
guidelines, hydroxyurea should be initiated in
adults with severe disease (3 painful crisis
per year, history of severe or recurrent SCA,
or with symptomatic chronic anemia/pain
affecting quality of life) and should be offered
to all children with SCA starting at 9 months
of age. In the United States, this recommenda-
tion appears to be associated with increased
hydroxyurea prescribing.48
Despite increased treatment acceptance,
major barriers to implementing hydroxyurea
treatment for all eligible patients remain.
Prominent barriers include (1) adverse effects
such as rash, alopecia, nail discoloration,
headache, nausea, and weight gain, unresolved
concerns for decreased fertility (especially in
males), and teratogenicity49-51; (2) deciding
the optimal timing of treatment initiation in
children; in Europe, concerns about unknown
and understudied effects of hydroxyurea,
including infertility and carcinogenesis, limit
hydroxyurea prescribing to children with
severe disease34,51-53; (3) prescriber discom-
fort and delay in initiating therapy for eligible
patients54; (4) poor patient adherence to a life-
long regimen34; and (5) lack of high-quality
evidence for use in patients with variant SCD
(compound heterozygotes) who comprise
one-third of all patients with SCD.55 Of
note, worries about carcinogenesis from
hydroxyurea arose in patients treated for
myeloproliferative neoplasms,52 which have a
baseline increased risk of hematologic malig-
nancy. The association of carcinogenesis with
hydroxyurea is not substantiated by the avail-
able literature. One study found a 2-fold
increased age-related risk of leukemia in
patients with SCD in California compared
with the general population, irrespective of
treatment.56 This finding may reflect the natu-
ral history of SCD in the emerging population
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Root cause:
Primary
treatments HSCT
gene therapy HbS mutation
HbF inducers
antisickling agents HbS polymerization
Downstream
sequelae
Secondary
treatments
Adhesion Inflammation Thrombophilia Oxidant
Antiplatelet
stress
IVIG Simvastatin Glutamine
agents
Propranolol Zileuton Rivaroxaban N-acetylcysteine
Rivipansel Regadenoson Apixaban Omega-3 FA
Crizanlizumab
FIGURE 2. Framework for categorization of current treatments for sickle
cell disease. This pyramid depicts a classification of treatment modalities into
primary treatments (that target the hemoglobin S (HbS) mutation and/or
polymerization) and secondary treatments (that target one of the down-
stream consequences of HbS polymerization). The primary treatments are
predicted to have more widespread effect because they treat the root
cause and prevent all downstream consequences of sickling. HbF ¼ he-
moglobin F; HSCT ¼ hematopoietic stem cell transplant; IVIG ¼ intrave-
nous immunoglobulin; Omega-3 FA ¼ omega-3 fatty acid.
of older adults with SCD. Long-term follow-
up of patients initiating hydroxyurea in child-
hood may help clarify whether concerns about
hydroxyurea’s carcinogenic potential are war-
ranted.31,57 Ultimately, hydroxyurea is not a
panacea for people with HbSS. Damage to
the kidney,58 brain,59 and spleen60 is not
entirely prevented with treatment.
Novel Antisickling Agents
Hemoglobin S polymerization is the first step in
the cascading pathophysiology of SCD. Hemo-
globin S polymerization is inhibited by agents
that (1) induce HbF (eg, hydroxyurea [discussed
previously], decitabine, pomalidomide, panobi-
nostat, INCB059872, and sodium butyrate), (2)
disfavor polymerization by preventing dehydra-
tion (senicapoc and magnesium), (3) delay pro-
duction of deoxyhemoglobin S by shifting the
oxyhemoglobin dissociation curve to the left
(increasing affinity of Hb for oxygen, eg, Aes-
103 and GBT440), (4) deliver carbon monoxide
to the RBC (pegylated carboxyhemoglobin),61
and (5) inhibit sickling via an unknown mecha-
nism (SCD-101 and Nicosan). SCD-101, a novel
botanical drug whose mechanism is unknown,
5

has a dose-dependent antisickling effect. In a
phase 1b dose-escalation study in patients with
SCA, SCD-101 was tolerated well and decreased
chronic pain and fatigue.62 Part B of this phase
1b clinical trial is a randomized, double blind,
placebo-controlled crossover study of SCD-101
in patients with SCA and is currently recruiting
(NCT02380079). Another antisickling agent
with an unknown mechanism of action, Nicosan
(or Niprisan) is a plant extract shown to decrease
painful crises in Nigerian patients.63,64 There are
no trials studying Niprisan in the United States.
Clinical trials investigating the use of the afore-
mentioned agents are enrolling patients (Table).
Long-term Transfusion Therapy
Long-term therapy with RBC transfusion is an
alternative to hydroxyurea. Strong evidence
guides the use of long-term RBC transfusions
for children with HbSS and abnormal to
prevent stroke.26,27 The multicentered Stroke
Prevention Trials in Sickle Cell Anemia
(STOP I and II) trials reported that long-
term transfusion therapy in children with
abnormal TCD reduced stroke risk and that
this salutary effect was lost when transfusions
were stopped. 26,27 The Stroke With Transfu-
sions Changing to Hydroxyurea (TWITCH)
trial found that transitioning from long-term
transfusion therapy to hydroxyurea, at the
maximum tolerated dose in children with
abnormal TCD but no severe vasculopathy,
was noninferior to long-term transfusions in
children and could be used as an alternative
to transfusions for primary prevention of cere-
brovascular disease.65
Long-term transfusion therapy is performed
as simple transfusions or partial or complete ex-
change transfusions (erythrocytapheresis). Risks
of long-term transfusion therapy include transfu-
sional iron overload (less so with exchange trans-
fusions), which accumulates over time and can
be life-threatening, alloimmunization, and trans-
mission of transfusion-associated infections.66-71
Delayed hemolytic transfusion reactions second-
ary to alloimmunization complicate 4% to 11%
of transfusions for SCD.67,72
Stem Cell Replacement/Modification
Therapies
Hematopoietic Stem Cell Transplant.
Allogeneic HSCT cures SCD by eliminating sickle
Hb production by replacing existing
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6 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
hematopoetic stem cells with cells from an alloge-
neic donor. Hematopoietic stem cell transplant is
used when the benefits of cure outweigh the risks
of transplant-associated toxicities and when a
suitable donor is available. Benefits of HSCT
include the physiologic normal erythropoiesis,
prevention of end-organ damage, and decreased
SCD-associated morbidity and mortality.73
Concerns about HSCT include patient selection
(based on age, disease severity, and end-organ
injury), risk of short-term toxicity (infection,
posterior reversible encephalopathy syndrome,
death), graft failure, possibility of long-term
adverse effects (graft-vs-host disease [GVHD],
infertility), selection of an effective and mini-
mally toxic preparative regimen (myeloablative
vs nonmyeloablative), and a limited donor
pool.73-75
Defining eligibility for HSCT is challenging
and is based on individualized analysis of benefits
and risks. Age is a strong determinant of success-
ful HSCT. In pediatric patients, matched sibling
donor transplants with myeloablative regimens
have been successful.76,77 Among 1000 HLA-
identical sibling HSCT recipients from a world-
wide cohort, age was a significant risk factor for
mortality. The overall survival of patients older
than 16 years was 80% compared with 95%
5-year overall survival in those younger than 16
years (P<.001).78 Tools to predict SCD severity
to determine transplant eligibility are limited
and predominantly include major SCD compli-
cations.79 In 2014, an international expert panel
recommended that HSCT with unrelated or hap-
loidentical grafts in a controlled trial setting be
considered for patients with severe complications
of SCD, including stroke, recurrent vaso-
occlusive crisis (>2 episodes per year), recurrent
priapism, impaired neuropsychological function,
stage I or II sickle cell lung disease,80 acute chest
syndrome, sickle nephropathy, bilateral prolifer-
ative retinopathy, osteonecrosis, or transfusion-
related alloimmunization.81 The panel also rec-
ommended that symptomatic patients be offered
transplant from available HLA-identical sibling
stem cells or HLA-identical sibling cord blood
as early as preschool age.81
The availability of a suitable donor is a pre-
requisite to HSCT for transplant-eligible
patients and a major barrier to treatment.
Only 10% to 20% of patients with SCD in
the United States have a matched sibling,
matched unrelated donor, or preserved cord
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NOVEL TREATMENTS FOR SICKLE CELL DISEASE
bloods available.74 Thus, recent approaches to
HSCT focus on expanding the donor pool by
using matched unrelated donors and haploi-
dentical donors.82-84 In children, matched un-
related donor recipients have lower 1- and 2-
year event-free survival of 76% and 69%,
respectively, and lower corresponding overall
survival of 86% and 79%.82,85 In a pilot multi-
center study (STRIDE [Study of Hematopoiet-
ic Stem Cell Therapy for Young Adults with
Severe Sickle Cell Disease]), related and unre-
lated donor HSCT with a reduced toxicity
conditioning regimen in 22 adults with severe
SCD, 1-year event-free and overall survival
were higher at 95%, without any graft failure
and very low rates of GVHD (2 patients with
acute grade 1 skin GVHD and 3 with chronic
GVHD).86 At present, cord blood donors are
too risky for use in SCD (SCURT [Sickle Cell
Unrelated Donor Transplant Trial] study).87,88
Haploidentical HSCT is experimental in chil-
dren and adultsdBMT CTN 1507
(NCT03263559) and National Heart, Lung,
and Blood Institute intramural 17-H-0069
(NCT03077542) are 2 trials investigating non-
myeloablative preparative regimens with bone
marrow or peripheral blood stem cell grafts,
respectively.89 Haploidentical HSCT is associ-
ated with higher transplant morbidity and
graft failure, but this approach continues to
be pursued because of the potential to consid-
erably expand the donor pool.78,83
Children undergoing matched sibling trans-
plants tolerate myeloablative regimens well.76,77
In adults, myeloablative regimen toxicity may
be prohibitive and needs further study. Although
reduced-intensity nonmyeloablative HSCTs were
initially associated with only transient donor
engraftment,84 long-term engraftment with a
stable mixed- and full-donor chimerism has
improved in subsequent studies (2014 National
Institutes of Health study and STRIDE, respec-
tively).86,90 Both myeloblative (NCT02675959,
NCT01590628, and NCT02179359) and non-
myeloablative (NCT01499888, NCT01850108,
and NCT03249831) strategies to restore either
normal or partial erythropoiesis, respectively,
are under investigation at a number of sites.90
Major concerns about HSCT remain.
Whether HSCT prolongs life for patients with
SCD is unclear.91 In a Belgian cohort, survival
in adults and children treated with hydroxyurea
was superior to those treated with HSCT.91
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Optimization of nonmyeloablative strategies
and strategies to expand the donor pool may in-
crease the availability of HSCT; routine reas-
sessments of a patient’s baseline SCD and the
risks of HSCT are thereby necessary.79 Infer-
tility is a risk for all patients undergoing
HSCT.92 Fertility preservation, even for very
young children, should be offered before treat-
ment. Finally, recommendations for asymp-
tomatic patients and those with compound
heterozygosity have not been made.73
Gene Therapy. Gene therapy is the “Holy
Grail” of SCD treatment and has long been
sought as a definitive cure. In 2017, Ribeil
et al93 reported that a 13-year-old boy with
HbSS disease had been cured with gene ther-
apy. This thrilling event marked the first time an
antisickling b-globin variant (bA-T87Q) had
been successfully transferred into a human pa-
tient. Recent technological breakthroughs, such
as in situ gene mutagenesis (eg, via CRISPR/
Cas9), are creating opportunities for genetic
manipulation (gene insertion, deletion, or
modification) by deleting the HbS mutation or
increasing HbF production through silencing a
repressor of HbF production (eg, BCL11A).94,95
After encouraging mouse studies of gene ther-
apy,96,97 2 clinical trials studying gene therapy
using a lentiviral vector in adults with ho-
mozygous or severe variant SCD are under
way (NCT02247843, NCT02186418). More
studies are needed to establish this therapy’s
durability and safety. A myeloablative condi-
tioning regimen followed by the infusion of
manipulated autologous stem cells is under
investigation.98
A major advantage of gene therapy over
HSCT is the ability to use autologous stem cells,
thus obviating the need to identify donors.
However, like HSCT, undergoing gene therapy
requires exposure to radiation and chemo-
therapy. Lentiviral transfer has not been associ-
ated with insertional carcinogenesis or
mutagenesis to date,99,100 but long-term studies
are needed to adequately assess this risk.
TARGETING DOWNSTREAM CONSE-
QUENCES OF HBS POLYMERIZATION
Antioxidant Therapy
L-glutamine. L-glutamine is an amino acid
precursor for nicotinamide adenine dinucleotide
7

(NAD) and is required for the formation of the
antioxidant reduced NAD (Figure 3). Nicotin-
amide adenine dinucleotide production is
adequate in patients with SCD, but erythrocyte
glutathione and glutamine levels are significantly
depleted.101,102 This decrease has been attrib-
uted to the increased oxidant burden in sickle
RBCs and higher L-glutamine consumption.103
Decreased L-glutamine levels lead to lower
NAD redox potential and impair erythrocyte
integrity, increase hemolysis, and deplete NO.
Glutamine depletion is a biomarker for hemo-
lysis and is independently associated with
pulmonary hypertension in patients with
SCA.101
The effect of L-glutamine in SCD has been
studied, but to validate its benefits and feasi-
bility in age- and genotype-specific popula-
tions, additional peer-reviewed evidence is
needed. In a prospective interventional study
of 7 adults with SCA, L-glutamine powder sup-
plementation for 4 weeks resulted in increased
RBC reducing potential and subjective
improvement in energy levels.104 In 2005, a
cross-sectional and prospective study of 9
adults with SCA found that L-glutamine sup-
plementation led to diminished adhesion of
treated RBCs to human umbilical vein endothe-
lial cells.104,105 In 2014, a 2:1 randomized,
placebo-controlled, double-blind phase 3 study
of L-glutamine oral powder in 230 patients (5-
58 years of age) with HbSS and HbS b0 thalas-
semia was conducted.106 Results of this trial
have not yet been published in a peer-
reviewed journal. Data available on the FDA
website show that patients receiving L-gluta-
mine had fewer painful events over the 48-
week study period (3 events vs 4 events;
P¼.008), lower incidence of hospitalization (2
events vs 3 events; P¼.005), a decreased dura-
tion of hospital stay (6.5 days vs 11 days;
P¼.022), decreased development of acute chest
syndrome (11.9% vs 26.9%; P¼.006), and a
lengthened median time from randomization
to first crisis (87 days vs 54 days; P¼.01). Treat-
ment effect was independent of hydroxyurea
use.107 These data formed the basis for FDA
approval in patients with SCD aged 5 years
and older. Although L-glutamine is approved
for all SCD types, the phase 3 study included
only patients with HbSS. Genotype-specific
subgroup analyses are not yet available, nor
are estimates of cost or feasibility.
n n
8 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
N-acetylcysteine. N-acetylcysteine (NAC) is
an antioxidant used as a mucolytic for respi-
ratory diseases that decreases dense cell and
irreversibly sickled cell formation in patients
with homozygous SCD.108 N-acetylcysteine
is converted to L-cysteine in the cytoplasm,
which increases glutathione levels. In a phase
2 study of 21 patients with SCA who were
older than 15 years, NAC restored gluta-
thione levels, decreased dense cell formation,
and led to a statistically insignificant
decrease in the number of painful crises.109
A pilot study is currently enrolling partici-
pants with HbSS to evaluate the effects of
intravenous NAC on plasma von Willebrand
factor parameters, redox, and RBC function
(NCT01800526).
a-Lipoic Acid and L-acetylcarnitine. A com-
bination of potent antioxidants, a-lipoic acid
and acetyl-L-carnitine, was given to 14 patients
with hemoglobinopathies (11 with SCD and 3
with HbH-Constant Spring) and significantly
improved the redox state of glutathione
(reduced:oxidized glutathionine) at 3 weeks.110
A phase 2 study in patients with SCA assessed
reduction in oxidant stress and pain crises using
these agents (NCT01054768); results are not
available yet.
Other Antioxidant Agents. Gum arabic,
omega-3 fatty acids, and curcumin are reported
to diminish oxidative stress in SCD but have not
achieved widespread clinical applicability to
date.111-113
Inhibition of Cellular Adhesion
Numerous novel antiadhesive agents that target
RBC-endothelial and leukocyte-endothelial in-
teractions are in development.
P-selectin Inhibitors. P-selectin mediates
leukocyte and erythrocyte adhesion to the
vascular endothelium and contributes to vaso-
occlusion in patients wth SCD.30,114 P-selectin
is stored in endothelial cell granules and is
released to the cell surface when stimulated by
histamine, thrombin, endotoxin, peroxides, or
hypoxia.6,114 In a transgenic mouse model
expressing human HbS, blocking or depleting
P-selectin decreased erythrocyte and leukocyte
adhesion.115,116 Crizanlizumab (SEG101) is a
humanized monoclonal antibody that binds to
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NOVEL TREATMENTS FOR SICKLE CELL DISEASE

FIGURE 3. Normal glutathione metabolism. Glutathione is an antioxidant that reduces reduced nico-
tinamide adenine dinucleotide phosphate (NAD[P]H) in the red cell. Glutathione is synthesized from the
amino acids glutamate, glycine, and, cysteine by the g-glutamylcysteine synthetase and glutathione syn-
thetase. In patients with sickle cell disease, glutathione and glutamine levels are low despite increased
availability of glutamate, cysteine, and glycine, resulting in increased oxidant stress. L-glutamine was
approved by the US Food and Drug Administration in 2017 to replenish the erythrocyte reducing po-
tential. H2O ¼ water; H2O2 ¼ hydrogen peroxide; NADP ¼ nicotinamide adenine dinucleotide
phosphate.

P-selectin and blocks P-selectin’s interaction
with P-selectin glycoprotein 1 on circulating
leukocytes. The Phase II, Multicenter, Ran-
domized, Placebo-Controlled, Double-Blind,
12-Month Study to Assess Safety and Efficacy of
SelG1 With or Without Hydroxyurea Therapy
in Sickle Cell Disease Patients With Sickle Cell-
Related Pain Crises (SUSTAIN) trial found that
high-dose crizanlizumab (5 mg/kg) resulted in a
45.3% decreased rate of crises per year (P¼.01)
and increased the time to the first crisis (4.07 vs
1.38 months; P¼.001) or second crisis (10.32
vs 5.09 months; P¼.02) compared with pla-
cebo.117 There were no differences in hemolytic
parameters between the interventional and
placebo arms, suggesting that treatment benefit
may be attributable only to modified cellular
adhesion. The reduction in annual crisis rate
was greater in patients not taking hydroxyurea
compared with those who were (50% lower vs
32.1% lower, respectively). The SUSTAIN trial
included patients aged 16 to 65 years and all
SCD genotypes, but 70% of study patients had
HbSS. Additional studies are therefore needed
to address use in pediatric patients and to assess
efficacy by genotype. Adverse events were
comparable between treatment and placebo
groups.
Pan-selectin Inhibitors. Rivipansel (GMI-
1070), a synthetic pan-selectin inhibitor that
inhibits cell-cell interactions and adhesion,
prolonged survival in Berkeley sickle cell
mice118 and was associated with significant
decline in intravenous opioid use (83% lower
opioid use compared with placebo) when
tested in 73 adults with SCA.119 A phase 3
trial of rivipansel safety and efficacy is
recruiting patients (NCT02187003).
Other Antiadhesive Therapies
Intravenous Immunoglobulin. In a sickle cell
mouse model, intravenous immunoglobulin
inhibited RBC-neutrophil and neutrophil-
endothelial adhesive interactions and
improved microcirculatory blood flow and
survival.120,121 A phase 2 study is currently
recruiting patients to evaluate the safety and
efficacy of intravenous immunoglobulin in pa-
tients with SCD within 24 hours of admission
with a pain crisis (HbSS and HbS b-thalassemia,
NCT01757418).

Mayo Clin Proc. n XXX 2018;nn(n):1-15 n https://doi.org/10.1016/j.mayocp.2018.08.001 9

www.mayoclinicproceedings.org

Heparin. Heparins are anti-inflammatory and
inhibit P-selectinemediated adhesion.122 A
randomized, double-blind trial found that tin-
zaparin, a low-molecular-weight heparin,
reduced the duration of vaso-occlusive crisis
without any severe bleeding complications.123 A
feasibility trial is currently recruiting participants
to assess the effect of unfractionated heparin in
acute chest syndrome (NCT02098993).
Propranolol. In a phase 1 dose-escalation
study, propranolol decreased sickle RBC
adhesion in a dose-dependent manner when
human RBCs from propranolol-treated pa-
tients with homozygous SCD were infused
into nude mice.124 Maximum inhibition was
achieved at a dose of 40 mg. No significant
heart rate changes or severe adverse events
were reported.124 Results from a double-blind
crossover phase 2 study (NCT01077921)
revealed decreased levels of measured soluble
biomarkers including E-selectin, P-selectin,
intercellular adhesion molecule 1 and vascular
cell adhesion molecule 1 in patients with ho-
mozygous SCD treated with propranolol
compared with placebo, but these decreases
were not statistically significant.125 This study
was not published in a peer-reviewed journal.
Because of the high prevalence of asthma in
children with SCD, a phase 1 study of pro-
pranolol in children without asthma was
initiated but eventually terminated due to
inability to recruit patients (NCT02012777).
No studies of propranolol in humans with
HbSS are currently open.
Antiplatelet Therapy
Activated platelets are common in SCD and may
contribute to vaso-occlusion by participating in
intercellular adhesion and forming multicellular
aggregates.126 Prasugrel is a third-generation
thienopyridine that inhibits adenosine
diphosphateemediated platelet activation and
aggregation by irreversibly binding to the
P2Y12 class of adenosine diphosphate recep-
tors. The Determining Effects of Platelet Inhibi-
tion on Vaso-Occlusive Events (DOVE) trial was
a phase 3, double-blind, placebo-controlled
study of prasugrel in children and adolescents
aged 2 to 17 years with HbSS that did not find
a reduced rate of vaso-occlusive crises with
prasugrel treatment.127 In a phase 1 study in
n n
10 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
patients with SCA, another antiplatelet agent,
eptifibatide, a platelet glycoprotein aIIbb3
antagonist, inhibited platelet aggregation and
favorably altered inflammatory mediators.128 A
phase 2 placebo-controlled trial reported the
safety of eptifibatide in 13 patients with SCD
with acute pain crises but did not find improve-
ment in recovery times or time to hospital
discharge.129 A secondary analysis revealed
that eptifibatide inhibited platelet aggregation,
platelet release, and platelet P-selectin expres-
sion and decreased platelet-leukocyte aggre-
gates and inflammatory markers.130 That
antiplatelet agent monotherapy does not benefit
patients with SCD suggests that other mecha-
nisms involved in vaso-occlusion may be more
prominent drivers of SCD pathophysiology.
However, more research with well-powered
studies is needed to definitively determine the
efficacy of antiplatelet agents for treating or pre-
venting pain.
Agents Affecting Vascular Tone
Intravenous magnesium, inhaled NO, and
sildenafil, agents that improve vascular tone
and endothelial dysfunction, have not reduced
the frequency or duration of painful crises in
patients with homozygous and variant
SCD.131-133
CHALLENGES AND PITFALLS
A lack of equitable National Institutes of Health
funding134 and small clinical trials contribute to
the limited clinical armamentarium against
SCD. Nevertheless, the development of novel
treatments for SCD is an area of active research.
Current evidence for many therapies is limited
by the need for age- and genotype-specific
research. The management of SCD is limited
by many unanswered clinical questions and
challenges, such as (1) treatment options for pa-
tients with SCD who are pregnant,135 (2) the
ethical dilemmas posed by the current state of
HSCT136,137 and gene therapy, especially for
asymptomatic patients and (3) optimum pain
management in a population faced with lifelong
episodes of acute and chronic pain that evolves
with age and is exacerbated by socioeconomic
stressors and age.138,139 Ironically, painda
substantial and bedeviling problem for patients,
their families, and their physicians alikedis,
with few exceptions,140 seldom specifically
targeted in therapeutic trials.
XXX 2018;nn(n):1-15 https://doi.org/10.1016/j.mayocp.2018.08.001
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NOVEL TREATMENTS FOR SICKLE CELL DISEASE
CONCLUSION
Disease-modifying therapies for SCD include
hydroxyurea, now FDA approved for adults
and children with homozygous SCD, and
long-term transfusions. Nearly 2 decades after
the approval of hydroxyurea, L-glutamine was
FDA approved with little published peer-
reviewed evidence and many remaining ques-
tions about its use and tolerability. Antisickling
gene therapy is an exciting and promising area
of research but is not yet established as safe or
efficacious. Allogeneic HSCT is the only cura-
tive treatment and has recently shown promise
in older adults as well. Early referral for evalua-
tion for HSCT is strongly encouraged for
patients with symptomatic SCD.
There is an unmet need for disease-
modifying therapies in SCD, and a great deal
of recent scientific discovery has led to the
development and testing of novel agents that
are in preclinical and clinical testing. In the
coming decades, these new approaches, once
optimized, may considerably brighten the
outlook for patients with SCD, their families,
and their physicians.
ACKNOWLEDGMENTS
We would like to thank our patients for giving
us the inspiration and motivation to learn
moredand do moredabout SCD.
Abbreviations and Acronyms: FDA = Food and Drug
Administration; GVHD = graft-vs-host disease; Hb = he-
moglobin; HSCT = hematopoietic stem cell transplant; NAC
= N-acetylcysteine; NAD = nicotinamide adenine dinucleo-
tide; NO = nitric oxide; RBC = red blood cell; SCA = sickle
cell anemia; SCD = sickle cell disease; TCD = transcranial
Doppler velocity
Potential Competing Interests: The authors report no
competing interests.
Correspondence: Address to Lydia H. Pecker, MD, Division
of Pediatric Hematology, Ross Bldg, Rm 1125, Johns Hop-
kins University School of Medicine, 720 Rutland Ave, Balti-
more, MD 21205 (lpecker1@jhmi.edu).
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