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Investigational therapies for sickle cell disease

Investigational therapies for sickle cell disease
Author:
Courtney Fitzhugh, MD
Section Editor:
Michael R DeBaun, MD, MPH
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 28, 2022.

INTRODUCTION — The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of ischemia-reperfusion injury of the organs, leading to cerebral infarcts; heart, lung, and kidney disease; pain that can be severe and debilitating; and other complications.

Hydroxyurea is the primary therapy to prevent these complications in children and adults with Hb SS and Hb S beta0 thalassemia. Hydroxyurea provides a myriad of well-documented clinical benefits, making it the first choice for children and adults with Hb SS and Hb S beta0 thalassemia. However, hydroxyurea has limitations, and not all individuals with SCD benefit from therapy. Additional therapies are needed for those who cannot take hydroxyurea or for whom hydroxyurea or one of the other disease-modifying therapies is ineffective. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

This topic reviews potential therapies for SCD that are in development or undergoing clinical investigation, including their rationale, preclinical data, and information from early clinical trials. It also discusses when these newer agents should be considered and when patients should be referred to be considered for therapy with a curative intent.

Separate topic reviews discuss existing management options in SCD including routine evaluations and treatments, hydroxyurea and other disease-modifying therapies, transfusions, and hematopoietic stem cell transplantation:

Management overview – (See "Overview of the management and prognosis of sickle cell disease".)

Comprehensive care for children – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

Pain management – (See "Acute vaso-occlusive pain management in sickle cell disease".)

Hydroxyurea – (See "Hydroxyurea use in sickle cell disease".)

Transfusion – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Transplant – (See "Hematopoietic stem cell transplantation in sickle cell disease".)

OVERVIEW

Timeline of drug development in SCD — Since the initial report of SCD, there have been few approved disease-modifying therapies, with the first drug, hydroxyurea, approved over 80 years later. The timeline of new SCD therapies has accelerated during the previous two decades, with the following history:

1910 – SCD first reported

1998 – First drug approved for SCD treatment (hydroxyurea)

2017 to 2019 – Three additional therapies approved (L-glutamine in 2017; crizanlizumab and voxelotor in 2019)

More agents are being developed and are in early phase trials. (See 'Pharmacologic therapies' below.)

Limitations of available therapies — The most common and debilitating complication experienced by individuals with SCD is acute vaso-occlusive pain. However, there are other risks for severe morbidity and early mortality due to chronic complications such as stroke, kidney failure, and cardiopulmonary disease [1,2]. Despite the remarkable efficacy of hydroxyurea, there are limitations to its use, and many questions remain unanswered:

Indications – The efficacy of hydroxyurea in individuals with Hb SC and Hb S beta+ thalassemia is unproven. Important clinical trial data have mostly included individuals with Hb SS and Hb S beta0 thalassemia. (See "Hydroxyurea use in sickle cell disease", section on 'Evidence for efficacy'.)

SafetyHydroxyurea has limited use in individuals planning to have children. It typically is not used in females attempting to conceive due to presumed teratogenic effects, although definitive evidence of teratogenicity is lacking [3]. It typically is not used in males attempting conception due to its impact on sperm count, although it has no significant impact on spermatogenesis when started during the pre-pubertal period [4,5]. (See "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)

EfficacyHydroxyurea reduces vaso-occlusive pain episodes, acute chest syndrome, and red blood cell transfusions by approximately 50 percent in adults with Hb SS and Hb S beta0 thalassemia. However, some individuals will continue to have acute pain episodes, other vaso-occlusive events, or both, despite adherence to properly administered hydroxyurea. Morbidity and mortality remain high in adults with SCD, even when treated with hydroxyurea [6]. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

The newer FDA-approved therapies may further reduce vaso-occlusive complications, improve anemia, and/or reduce hemolysis, but none of them have been demonstrated to abate progressive heart, lung, kidney, or central nervous system disease or to provide a cure for the disease. Additionally, some carry high costs and burdens such as the requirement for intravenous administration. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Disease-modifying medications'.)

Regular blood transfusion therapy, with a goal to decrease the Hb S level <30 percent or 50 percent, is indicated in some individuals, but transfusions also carry significant costs and burdens. (See 'Transfusions' below.)

New therapies and multi-modality approaches are needed to prevent acute vaso-occlusive pain episodes, attenuate progressive organ damage (including brain, heart, lung, and kidney), and increase life expectancy, as well as therapies that can be used in individuals with other compound heterozygous SCD (sickle beta+ thalassemia, hemoglobin SC disease). Further, no disease-modifying therapy, other than monthly blood transfusion therapy, can be used for pregnant women, a period with the highest incidence rates of acute pain and acute chest syndrome [7]. As new therapies are being considered, strategies should be included that can be used during pregnancy, the period with the highest rate of vaso-occlusive pain and acute chest syndrome.

Categories of SCD therapies — Therapies for SCD can be categorized as pharmacologic or curative.

Pharmacologic therapies are medications that must be taken on a regular basis. There are several steps in the vaso-occlusion process that can be targeted. Many of these are under investigation, as summarized in the discussions below. Examples include:

Fetal hemoglobin induction – (See 'Increasing Hb F' below.)

Inhibiting sickle hemoglobin polymerization – (See 'Reducing Hb S polymerization' below.)

Reducing interactions between sickle cells, neutrophils, and/or vasculature – (See 'Decreasing cell adhesion' below.)

Decreasing oxidative stress – (See 'Decreasing oxidative stress' below.)

In some cases it may be possible to target several of these processes simultaneously, which might produce additive or synergistic effects.

Curative therapy refers to hematopoietic stem cell transplant (HSCT), including standard allogeneic HSCT, alternative donor allogeneic HSCT, and modified autologous HSCT, using autologous hematopoietic stem cells (HSCs) that have been treated with gene therapy or gene editing techniques. As noted below, we consider all HSCT therapies to be investigational in SCD because the optimal approach to their use remains unclear, especially for children. (See 'Therapies with curative intent' below.)

How to select and sequence therapies

FDA-approved agents — US Food and Drug Administration (FDA)-approved agents, along with indications for use, supporting data, and appropriate sequence, are summarized below and discussed in detail in separate topic reviews:

Hydroxyurea – Should be offered to all adults and children with Hb SS and Hb S beta0 thalassemia at nine months of age. (See "Hydroxyurea use in sickle cell disease".)

L-glutamine – May be offered to children ≥5 years or adults who continue to have pain episodes despite hydroxyurea or who cannot take hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'L-glutamine (pharmaceutical grade)'.)

Crizanlizumab – May be offered to adolescents ≥16 years or adults who continue to have pain episodes despite hydroxyurea or who cannot take hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Crizanlizumab'.)

Voxelotor – May be offered to children ≥4 years or adults who have symptomatic or severe anemia related to their SCD.

Transfusions — Transfusions can be used to treat acute anemia or as prophylaxis against complications, as summarized briefly here and in detail separately. The goal of chronic (regular) transfusion therapy or exchange transfusions is to keep the percent of Hb S <30 percent. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Acute vaso-occlusive events – Transfusions are used in the acute setting for stroke, acute chest syndrome, multi-organ failure, symptomatic anemia, hepatic sequestration, or splenic sequestration.

Prophylaxis – Transfusions are used preoperatively and during pregnancy. Chronic transfusions are used for stroke prevention in at-risk individuals, and for certain other recurrent vaso-occlusive complications (eg, acute chest syndrome) if they continue despite hydroxyurea and the individual is eligible for therapy.

Pain control – We consider a defined period of chronic transfusions (typically 6 to 12 months) in adolescents and adults with recurrent acute pain episodes that are not improved with disease-modifying therapy. Transfusion therapy is often coupled with mental health counseling for assessment of the presence and treatment of depression and anxiety. However, transfusions carry risks and burdens, as discussed separately. We agree with a 2020 guideline from the American Society of Hematology (ASH) that suggests monthly (regular) transfusions not be used as a first-line strategy to prevent or reduce recurrent acute pain episodes [8]. (See "Transfusion in sickle cell disease: Management of complications including iron overload".)

When to consider investigational therapies — Individuals whose disease is well controlled with available therapies, who have good quality of life, and who wish to avoid the burdens and unknown risks of investigational therapies, may continue their current treatment. For others, the question of investigational therapies may be further explored.

Investigational therapies that have not been approved by the FDA or a comparable regulatory agency are administered as part of a clinical trial. FDA-approved therapies may be administered for an off-label indication that is considered investigational. The decision to participate in a clinical trial depends on what clinical trials are available at the time and the expert opinion of a sickle cell disease specialist.

Clinicians and patients should familiarize themselves with the details of the trial (or off-label use) before participating, including available alternatives, possible benefits, possible risks, and trial design and oversight. In some cases, individuals and their families may need to travel to specialized SCD centers that are conducting research to receive investigational therapies.

The risk-benefit calculation differs substantially between pharmacologic therapies, which can be discontinued if unhelpful or for side effects, versus curative therapies, which carry a much higher up-front risk and the possibility for cure. Considerations for each type of therapy are discussed below.

Pharmacologic – Pharmacologic therapies include a number of drugs directed at various biologic targets to improve disease outcomes, typically focused on decreasing the incidence of acute vaso-occlusive pain (see 'Pharmacologic therapies' below). Our approach is to reserve investigational pharmacologic therapies for children and adults who want to participate in clinical trials and where the potential risk-benefit ratio favors trial participation.

Curative – Overall survival is much higher in children with SCD than adults (in high-income settings, median survival to 18 years of nearly 99 percent) [9,10]. Based on the high survival rate, coupled with poorly defined risk of death and long-term health effects of curative therapy, our approach is to reserve hematopoietic stem cell transplant (HSCT; myeloablative matched related donor transplant or non-myeloablative haploidentical donor transplant with post-transplant cyclophosphamide) for children with cerebral infarcts (stroke or silent cerebral infarcts), or progressive heart, lung, or kidney disease that does not respond to disease-modifying therapy [11].

Adults with repetitive pain episodes, recurrent priapism events, persistent acute complications, cerebral infarcts, or progressive heart, lung, or kidney disease that does not respond to disease-modifying therapy should at least be informed about investigational curative therapies. (See 'Overview of curative therapies' below.)

PHARMACOLOGIC THERAPIES — Investigational therapies should be considered only as part of a clinical trial. Drug trials for the most part focus on painful episodes as an endpoint, although drugs that reduce vaso-occlusive pain may also reduce other vaso-occlusive complications. Resources for determining which trials are available as well as recruiting, entry criteria, and other aspects of trial oversight are limited. The clinicaltrials.gov website is the best resource for trial review. As noted below, referral to an expert center that conducts high-quality clinical trials in SCD, including curative therapies, may be the best approach to ensuring that patients and their families receive the most comprehensive and balanced information about available trials. (See 'Overview of curative therapies' below.)

General information about the types of strategies being explored is summarized in the following sections.

Increasing Hb F — Fetal hemoglobin (hemoglobin F [Hb F]) is comprised of alpha globin chains and gamma globin chains, which do not contain the sickle cell variant (present only in beta globin chains). Increases in Hb F reduce the proportion of sickle hemoglobin, and this reduction in turn reduces the abnormal polymerization of hemoglobin molecules. (See 'Reducing Hb S polymerization' below.)

Increasing Hb F was initially thought to be the primary mechanism of action of hydroxyurea in SCD, although other contributing mechanisms have subsequently been proposed. (See 'FDA-approved agents' above and "Hydroxyurea use in sickle cell disease", section on 'Mechanism of action'.)

Other drugs are under development to increase Hb F by a variety of mechanisms:

Epigenetic changes – Drugs that de-repress gamma globin gene expression via epigenetic mechanisms (DNA methyltransferase (DNMT) inhibitors, histone deacetylase [HDAC] inhibitors) [12-17]. Of these, decitabine appears the most promising, but data are very limited [16]. Other epigenetic drugs including sodium dimethyl butyrate, vorinostat, and an inhibitor of lysine-specific demethylase (LSD-1) did not significantly elevate Hb F or were terminated early.

Immunomodulatory changes – In mouse models, the immunomodulatory agent, pomalidomide, led to modest increases of Hb F similar to hydroxyurea, with preserved bone marrow function and enhanced erythropoiesis [18]. One phosphodiesterase-9 inhibitor (IMR-687) also increased Hb F and decreased hemolysis [19]. Cilostazol (OPC-13013) is a reversible type III phosphodiesterase inhibitor with antiplatelet and vasodilating properties. In vitro, cilostazol induced RBC differentiation and Hb F production [20]. In a murine model, it led to gamma globin mRNA upregulation and an increase in Hb F-producing RBCs.

Curative therapies that increase Hb F levels are also being pursued. (See 'Gamma globin upregulation via targeting BCL11A' below.)

Reducing Hb S polymerization — Normal hemoglobin remains soluble in the cytoplasm of red blood cells (RBCs) during repeated cycles of oxygenation and deoxygenation. In contrast, Hb S polymerizes when deoxygenated, leading to precipitation and gel formation within the cell. The rate of polymerization depends on the intracellular Hb S concentration. These polymers dramatically reduce RBC deformability and cause damage to the RBC membrane.

Once polymerization occurs, polymerization-induced membrane damage leads to cellular dehydration, which in turn further increases the Hb S concentration, resulting in a cycle of worsening polymerization. This creates a population of very dense cells that are much more prone to sickling and contribute disproportionately to vaso-occlusion. (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

Several agents are under investigation to inhibit Hb S polymerization, through one or more of the following mechanisms [21]:

Increasing Hb F production – (See 'Increasing Hb F' above.)

Activating pyruvate kinase – (See 'Pyruvate kinase activation' below.)

Directly interfering with polymerization – (See 'Increasing O2 affinity of Hb S' below.)

Improving cellular hydration – (See 'Increasing RBC hydration' below.)

Improving oxygen delivery to RBCs – (See 'Increasing oxygen delivery' below.)

Voxelotor is a US Food and Drug Administration (FDA)-approved agent that directly inhibits Hb S polymerization. (See 'FDA-approved agents' above.)

Pyruvate kinase activation — The pathophysiology of SCD involves sickle hemoglobin polymerization upon deoxygenation. (See 'Reducing Hb S polymerization' above.)

RBCs with sickle hemoglobin are prone to deoxygenation; they have decreased oxygen affinity due to increased 2,3-diphosphoglycerate (2,3-DPG). (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

Thus, increasing oxygen affinity by manipulating 2,3-DPG levels might reduce Hb S polymerization. This is feasible because 2,3-DPG levels are controlled by the RBC enzyme pyruvate kinase (PK), and small molecule activators of PK are under study. (See "Pyruvate kinase deficiency", section on 'PK enzymatic function'.)

Two agents that increase PK activity and decrease 2,3-DPG levels are under study:

Mitapivat (MAG-348)

Etavopivat (FT-4202)

A phase 1 dose-escalation study of mitapivat in 16 patients reported that at the 50 mg BID dose level, mean hemoglobin increased by 1.2 g/dL compared to baseline [22]. There were dose-dependent increases in ATP and decreases in 2,3-DPG levels and improvements in hemolysis markers, with a tolerable safety profile. These results were confirmed in a study involving an additional nine patients [23].

Mitapivat can also be used to treat PK deficiency because it can increase the activity of dysfunctional variants of PK. (See "Pyruvate kinase deficiency", section on 'Treatment'.)

Etavopivat has shown promise in decreasing 2,3-DPG levels and increasing oxygen affinity in nonhuman primates and healthy volunteers [24,25]. RBCs collected from patients treated with etavopivat displayed increased Hb-oxygen affinity and reduced sickling under deoxygenation. Clinical trials are ongoing.

Increasing O2 affinity of Hb S — A small molecule that binds noncovalently to Hb S and increases its oxygen affinity was identified using an in silico screening strategy [26]. In a mouse model, this compound decreased sickling and increased hemoglobin levels [27]. This compound is being pursued clinically, with initial testing in healthy volunteers [28].

Increasing RBC hydration — Ion transport channels in the red blood cell (RBC) membrane control hemoglobin concentration by regulating the amount of intracellular solutes and free water. The RBC membrane has channels for potassium (K), sodium (Na), chloride (Cl), and other solutes, as discussed in detail separately. Increasing RBC hydration is a potential means of decreasing Hb S polymerization by decreasing its concentration in the RBC. (See "Control of red blood cell hydration".)

The Gardos channel (a calcium-activated K channel) is an attractive target for reducing Hb S concentration because Gardos channel inhibitors are already in clinical use for other indications. (See "Control of red blood cell hydration", section on 'Calcium-activated potassium channel (Gardos channel)'.)

Senicapoc (ICA-17043) is a highly potent Gardos channel inhibitor with good preclinical evidence of efficacy in improving RBC hydration. In a 2011 trial that randomly assigned 289 individuals with SCD to receive placebo or senicapoc, laboratory parameters improved (hemoglobin, cell hydration) but there was no reduction in pain episodes [29]. The hemoglobin response with senicapoc was similar to that with 900 mg voxelotor; although, larger reductions in markers of hemolysis were seen after treatment with senicapoc [30].

The Gardos channel inhibitor clotrimazole was previously studied in five individuals with SCD without clinical improvement [31].

N-methyl D-aspartate (NMDA) receptors are upregulated in RBCs of patients with SCD, and calcium uptake via these non-selective cation channels has a major impact on RBC hydration and Hb S polymerization. In vitro treatment of RBCs from individuals with SCD using the NMDA receptor inhibitor memantine led to RBC hydration and reduced sickling [32]. A study of the safety, tolerability, and efficacy of memantine as a long-term treatment of SCD is ongoing.

Increasing oxygen delivery — Sanguinate (pegylated bovine carboxyhemoglobin) is designed to deliver carbon monoxide as well as oxygen to tissues. Sanguinate has also been shown in vitro to deliver oxygen and carbon monoxide to sickled RBCs, reversing sickling [33]. A study involving 24 adults with homozygous SCD concluded that Sanguinate was safe [34]. A study using Sanguinate to treat vaso-occlusive pain has been completed.

Decreasing inflammation

Decreasing cell adhesion

Blocking selectin binding — Selectins are cell-surface adhesion molecules expressed on endothelial cells (E-selectin), white blood cells, and platelets (P [for platelet]-selectin) that may contribute to increased adhesion between blood cells and the microvasculature that promotes vaso-occlusion. (See "Pathophysiology of sickle cell disease", section on 'Adhesion of sickled cells to the vascular endothelium'.)

Crizanlizumab is a P-selectin-blocking monoclonal antibody therapy that was approved by the FDA in late 2019. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Crizanlizumab'.)

Rivipansel (GMI-1070) is a small molecule pan-selectin inhibitor. In a trial that randomly assigned 76 patients with SCD (ages 12 to 60 years) to receive rivipansel or placebo intravenously every 12 hours for up to 15 doses, there was no difference in the time to resolution of vaso-occlusive events, defined by either a sustained decrease in pain score, transition to oral analgesia, or hospital discharge [35]. However, unpublished results suggest some improvements, such as shorter times to hospital discharge and decreased duration of opioid use. Adverse events in the published trial were largely related to complications of SCD and were similar between the groups, with the exception of one episode of transient acute generalized exanthematous pustulosis (AGEP) in a patient who received rivipansel [35]. (See "Acute generalized exanthematous pustulosis (AGEP)".)

Antiinflammatory heparinoid (sevuparin) — Sevuparin is a short heparinoid altered to remove its anticoagulant properties while maintaining its antiinflammatory, anti-aggregation, and anti-adhesive properties. In a trial that randomly assigned 144 adults with SCD to receive sevuparin or placebo intravenously for two to seven days, there was no significant difference between groups in the median time to resolution of vaso-occlusive pain [36]. Sevuparin was well-tolerated. The observation that sevuparin did not attenuate recovery to baseline for acute vaso-occlusive pain events does not mean therapy will be ineffective for pain prevention, just that sevuparin therapy is not beneficial for abating a severe vaso-occlusive pain episode requiring hospitalization. Further research in this area is needed.

Decreasing neutrophil interactions — Neutrophil interactions with RBCs and endothelial cells could contribute to vaso-occlusion by creating a nidus of adhesion and retarded blood flow. (See "Pathophysiology of sickle cell disease", section on 'Inflammation'.)

Decreases in neutrophil counts may be one of mechanisms by which hydroxyurea reduces vaso-occlusion. (See "Hydroxyurea use in sickle cell disease", section on 'Mechanism of action'.)

Intravenous immune globulin (IVIG) has been studied to improve outcomes of vaso-occlusive pain. In a mouse model of SCD, IVIG decreased neutrophil adhesion to the endothelium and neutrophil interactions with RBCs [37,38]. Preliminary studies in children and adolescents with SCD suggest a trend towards shorter duration of vaso-occlusive pain with IVIG, although opioid use was not dramatically affected [39]. Administration of recombinant TGF-β1 administration decreased TNFα-induced leukocyte rolling, extravasation, and adhesion in a murine SCD model [40]. On the other hand, inhibition of TGF-β increased those factors.

Decreasing sickle RBC-endothelial adhesion

Recombinant ADAMTS13 – Ultralarge von Willebrand factor (ULVWF) multimers promote sickle RBC-endothelial adhesion. The metalloprotease ADAMTS13 cleaves ULVWF multimers. In one study, the ratio of ADAMTS13 to VWF:Ag was decreased in individuals with SCD, especially during a pain episode [41]. In a murine model of SCD vaso-occlusion, administration of recombinant ADAMTS13 reduced hemolysis and inflammation in the lungs and kidneys [42]. A clinical trial is ongoing.

Olinciguat – Olinciguat is a soluble guanylyl cyclase. In a mouse model of SCD, olinciguat improved survival and biomarkers of leukocyte-endothelial cell interactions and endothelial cell activation following treatment with tumor necrosis factor (TNF)-alpha [43]. A clinical trial is ongoing.

Decreasing inflammasome activation (canakinumab) — Inflammasomes are cytosolic multiprotein oligomers of the innate immune system that promote inflammation. Activation of inflammasomes leads to an inflammatory cascade that includes cleavage of pro-interleukin-1 beta (pro-IL-1b) into its active form, IL-1b, thereby inducing other inflammatory responses.

Canakinumab is a monoclonal antibody that inhibits IL-1b. In a randomized trial involving 49 individuals with SCD ages 8 to 20 years who had two or more vaso-occlusive events in the previous year, treatment with canakinumab for 24 weeks led to a modest decrease in the number of hospitalizations (mean, 0.9 versus 1.1 per patient), a shorter average duration of hospitalization (mean 6 versus 16; maximum 37 versus 127), and fewer days of opioid use (27 versus 48 days) [44]. Clinically meaningful pain reductions recorded by electronic diary were not statistically different in the canakinumab group compared to the placebo group. Markers of inflammation including high-sensitivity C-reactive protein, total leukocyte count, and neutrophils showed greater reductions in the canakinumab group. Therapy was well tolerated without an increase in infectious complications.

Decreasing neutrophil activation — Abnormal neutrophils may contribute to thromboinflammation in SCD. Annexin A1 (AnxA1) enables resolution of inflammation through formyl peptide receptors (FPR). In a mouse model of SCD, administration of the AnxA1 mimetic peptide AnxA1Ac2-26 increased blood flow cessation time in cerebral venules and arterioles [45]. This effect was reversed in SCD mice that were neutropenic prior to peptide administration, suggesting the decreased flow-cessation time in SCD mice is neutrophil dependent.

Decreasing platelet binding — Platelet activation is increased at baseline in SCD, and it is further increased during vaso-occlusive events, leading to the hypothesis that blocking platelet function might decrease vaso-occlusion. However, two randomized trials failed to show a benefit. A 2022 trial comparing the platelet adenosine diphosphate (ADP) P2Y12 inhibitor ticagrelor versus placebo in children with SCD did not show a statistically significant reduction in pain episodes or other endpoints (annualized rate of vaso-occlusive pain episodes, 2.74 with ticagrelor and 2.60 with placebo; rate ratio 1.06;, 95% CI 0.75-1.50) [46]. The 2016 DOVE trial evaluating the ADP P2Y12 inhibitor prasugrel also did not show a meaningful reduction in vaso-occlusive episodes [47].

Decreasing oxidative stress — Oxidative stress might contribute to vaso-occlusion by affecting the vasculature (vascular tone or adhesivity). (See "Pathophysiology of sickle cell disease", section on 'Vasoconstriction' and "Pathophysiology of sickle cell disease", section on 'Hypercoagulable state'.)

Oral L-glutamine is an FDA-approved agent for SCD that likely reduces oxidative stress by increasing the relative amount of reduced nicotinamide adenine dinucleotides in sickle RBCs [48]. L-glutamine decreases the frequency of hospitalizations for vaso-occlusive pain, even in individuals taking hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Other agents that might reduce oxidative stress are under investigation:

Inhibitor of cathepsin B – Investigators have reported abnormal retention of mitochondria in the RBCs of some individuals with SCD and in a mouse model [49,50]. Autophagy dysregulation may be responsible for the abnormal mitochondrial retention. Cathepsin B, a negative regulator of autophagy, was found to be overexpressed in the reticulocytes of patients with SCD and in the mouse model, and unpublished reports suggest that the cathepsin B inhibitor E64d might be a therapeutic target.

L-arginine – L-arginine is the substrate for nitric oxide production, and it might decrease oxidative stress in SCD. In a 2022 randomized trial in 66 children with SCD experiencing a pain episode with or without acute chest syndrome treated with arginine or placebo, those assigned to arginine had improvements in cardiopulmonary parameters including tricuspid regurgitant jet velocity and systolic blood pressure [51]. Another earlier study also noted in vitro effects but did not mention clinical improvement [52].

Decreasing hemolysis (hemopexin) — Hemolyzed sickle RBCs release heme, which induces expression of pro-inflammatory adhesion molecules and cytokines by endothelium and blood cells, promoting vaso-occlusion.

Hemopexin scavenges heme in plasma. In a murine model of SCD, injection of free hemoglobin induced vaso-occlusion [53]. Hemopexin administration prevented or decreased hemoglobin-induced and hypoxia/reoxygenation-induced vaso-occlusion in a dose-dependent manner. Hemopexin was given safely to rats and nonhuman primates. A clinical trial is ongoing.

THERAPIES WITH CURATIVE INTENT

Overview of curative therapies — Traditional allogeneic hematopoietic stem cell transplant (HSCT) and modified approaches to HSCT (gene therapy, gene editing) are the only potentially curative treatments for SCD; none of the pharmacologic agents that can be offered to individuals with SCD offers a cure. As noted above, we consider all curative therapies for SCD to be investigational, although others may consider this view to be conservative [54]. (See 'When to consider investigational therapies' above.)

The following considerations apply:

Informed consent – As noted above, the potential benefit of curative therapies must be carefully balanced with the risks of life-threatening complications and other morbidities of hematopoietic stem cell transplantation. Individuals with SCD should have the opportunity to understand what investigational therapies are available (pharmacologic and curative) and their risks and benefits. (See 'When to consider investigational therapies' above.)

Some transplant centers use HSCT in individuals with SCD outside of a clinical trial. However, we consider all forms of HSCT in SCD to be investigational because the optimal approach has not been determined. This includes the stem cell source (bone marrow, peripheral blood, or cord blood), the donor (matched related, haploidentical related, matched unrelated, or modified autologous hematopoietic stem cells [HSCs]), the conditioning regimen (myeloablative or non-myeloablative), and post-transplant care. The approach that maximizes benefit and minimizes adverse health effects (short, intermediate, and long-term) is unknown. Patients with SCD should have the opportunity to discuss risks and benefits of HSCT with their primary hematologist as well as experts at a center that performs transplant and clinical trials of pharmacologic therapy to better understand whether to pursue an HSCT evaluation.

The HSCT evaluation does not necessarily imply that HSCT is indicated. It is a consultation and an opportunity to understand the procedure, expected outcomes, and in some cases, to determine whether a sibling is a potential donor or whether there are other donor options (including modified autologous HSCs) that can be pursued.

Appropriateness – We are most likely to consider curative therapy in children and adults with complications of SCD associated with early mortality or severe morbidity. This includes the following complications not responsive to standard therapies:

Strokes [55]

Life-threatening acute chest syndrome

Progressive heart disease [56,57]

Progressive lung disease [58]

Progressive kidney disease [59-62]

Life-limiting pain

Recurrent priapism

Patient and family values and preferences carry significant weight in these decisions due to the investigational nature of curative therapies and the high up-front risks. (See 'Candidates for HSCT' below and 'Gene therapy and gene editing' below.)

Oversight – Clinical trials evaluating curative therapy should only be pursued if they have appropriate strong research governance oversight (typically including registration on clinicaltrials.gov). This includes institutional review board (IRB) review and involvement of a data safety monitoring board (DSMB) to ensure appropriate stopping rules for excess deaths, graft failure, or severe chronic graft-versus-host disease (GVHD).

In children, the IRB and DSMB must adhere to the code of federal regulation (CFR) requirement for research greater than minimum risk (45 CFR § 46.405[b]), which states that the relationship between anticipated benefit and risk must be at least as favorable as available alternative approaches [63]. In children in the United States and Europe, survival to age 18 with standard therapy is 99 percent; thus, investigational curative therapies must be at least as good as standard therapy or attenuate progressive effects on the brain, heart, lung, or kidney. This CFR requirement does not apply to adults, and most adults will meet broad clinical trial entry criteria for curative therapy trials.

Given the shortened life-span of adults with SCD, we are in favor of adults being informed of all clinical trial options for curative therapy that have appropriate DSMB and with stopping rules in place [6]. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

Approach – The most well-established form of curative therapy is matched related donor HSCT using myeloablative conditioning. This approach has the longest follow-up period. However, myeloablative therapy is associated with intermediate- and long-term sequelae that have not been rigorously studied and may be too toxic for adults. Due to these limitations, non-myeloablative matched related donor transplant has been developed primarily for adults with SCD, with significant success, although experience is somewhat limited. (See 'Allogeneic HSCT (matched related or alternative donor)' below.)

Expansion of the non-myeloablative matched related donor transplant protocol to children is ongoing as part of a clinical trial.

Ensuring that clinical trials meet these criteria is a time-consuming process, and resources to assist in reviewing clinical trials (eg, on clinicaltrials.gov) are limited. The clinicaltrials.gov website allows filtering on various trial attributes (age group, recruiting); nevertheless, the number of available trials can be large and in flux. Perhaps the best way to ensure that all individuals interested in pursuing these therapies can reasonably weigh their options is to refer to a center where experts in SCD and in HSCT can each provide consultation and guidance.

There are few premier transplant centers that are developing novel curative therapies based on preclinical models, and we advise our patients, especially children, to seek out these resources rather than enrolling in small, single-center trials that cannot provide this level of informed consent and research oversight. The referral often will be to a different center from the one where the patient receives their primary SCD care; this has the advantage of providing additional guidance to the patient and family without the risk of bias introduced by self-referral.

Regardless of the type of HSCT, few studies have documented the intermediate and long-term health effects of curative therapy. Late effects studies for patients with SCD are needed to evaluate the impact of the various types of curative therapy on organs that are associated with a high risk of early morbidity and mortality, including hematologic malignancy, particularly acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), heart, lung, kidney, and brain, as well as how curative therapy impacts pain, fertility, and quality of life.

Further studies are indicated to evaluate established and unforeseen sequelae of conditioning regimens required for curative therapy for SCD. Multi-center long-term health effects studies for SCD are underway(See "Hematopoietic stem cell transplantation in sickle cell disease", section on 'Clinical experience/HCT outcomes'.)

Allogeneic HSCT (matched related or alternative donor) — Allogeneic hematopoietic stem cell transplant (HSCT) is potentially curative for SCD because it replaces the individual's HSCs with HSCs that carry normal beta globin genes or that are heterozygous for the sickle mutation (from a donor with sickle cell trait). (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Candidates for HSCT — HSCT is available to individuals who have a suitable donor and for whom the potential benefits outweigh the risks of serious transplant-related morbidity and mortality. Encouraging results are emerging for human leukocyte antigen (HLA)-matched sibling HSCT in children, using either myeloablative conditioning (high-dose chemotherapy to eliminate the patient's bone marrow and allow it to be replaced with donor hematopoietic cells) or non-myeloablative conditioning (immunoablative therapy to decrease the incidence of graft rejection and graft-versus-host disease [GVHD]) [64-66]. However, the vast majority of patients with SCD do not have HLA-matched sibling donors.

For individuals who lack an HLA-matched related donor, another option is an alternative donor such as umbilical cord blood, a matched unrelated donor, or a haploidentical donor (including a parent, child, or sibling). Clinical experience with alternative donor HSCT remains limited, and many experts consider HSCT to be an investigational therapy that should only be performed in the context of a clinical trial [67]. This is mainly due to the major and life-threatening toxicities of allogeneic HSCT including acute and chronic GVHD and immunosuppression needed to prevent GVHD.

Many physicians taking care of patients with SCD have adopted a wait-and-see approach to HSCT because of the variability in the clinical course of SCD, the uncertainty in identifying patients who are most likely to have severe disease complications, the risks associated with the procedure, and the possibility that investigational therapies with fewer toxicities may become available in the reasonably near future. Decisions should be made based on response to pharmacologic therapy, perceived benefits and risks to the individual patient, access to clinical trials, and proper education of the patient and family, ideally by a transplant team for those individuals considered to have more severe disease.

Donor selection, conditioning regimens, alternative donors, and outcomes from clinical studies are presented separately. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Concern about myeloid malignancy in allogeneic HSCT — Myeloid malignancies have been reported following allogeneic HSCT, particularly in adults when therapy was used to produce mixed donor chimerism as opposed to full donor chimerism and following graft rejection. Studies using these platforms have reported 5 of 120 individuals (approximately 4 percent) developed MDS or AML after haploidentical or HLA-matched sibling HSCT for SCD [68,69]. On the other hand, in a subsequent report in 900 SCD HSCT recipients, most of whom were children who received HLA-matched related donor HSCT with a myeloablative conditioning regimen with the goal of full donor chimerism, the rate of MDS/AML was <0.5 percent [70]. The pathogenesis of myeloid malignancy development following HSCT or HSCT with gene therapy/gene editing in individuals is unknown and warrants further investigation. (See 'Concern about myeloid malignancy in gene therapy studies' below.)

Gene therapy and gene editing — Gene therapy (introducing a new gene) and gene editing (altering the sequence of an endogenous gene) have the potential to cure SCD [71,72]. Unlike allogeneic HSCT, these approaches modify the person's own HSCs, and concerns about GVHD do not apply. Typically, the endogenous HSCs are harvested, manipulations are done in the laboratory, and the cells are reinfused as part of an autologous HSCT.

Several approaches are under investigation, including:

Providing a corrected beta globin gene.

Providing a modified beta globin gene that has "corrective" properties.

Altering the normal hemoglobin switching program to revert to the fetal program, which uses the gamma globin gene to make fetal hemoglobin (Hb F) instead of the beta globin gene, which makes adult hemoglobin (Hb A).

In vitro studies and animal models have provided evidence for the feasibility of these approaches [73-78]. However, issues remain related to the safety and efficacy of the delivery viruses (or other delivery methods).

Other areas of active research include whether alternatives to myeloablative therapy can be used to prepare the individual for infusion of the autologous HSCs, or whether the gene therapy or gene editing construct can be delivered directly to the patient rather than to their HSCs in the laboratory [79]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'In vitro versus in vivo transduction'.)

As with other autosomal recessive conditions, it is not necessary to completely eliminate expression of the disease gene. Based on a model developed in the allogeneic setting, correction of approximately 20 percent of HSCs appears sufficient to reverse the sickle phenotype due to vast differences in red blood cell (RBC) survival between healthy RBCs and sickle RBCs [80].

Beta globin gene correction — The sickle cell variant is a single point mutation, and reversion to the wild-type sequence at one or both alleles of the beta globin gene (HBB) locus could convert SCD to sickle cell trait, a benign carrier condition, or to normal adult hemoglobin (Hb A).

Gene correction (which takes advantage of homology-directed repair) and gene editing are processes by which a wild-type beta globin gene is used as a template for endonucleases to "repair" the mutant sequence (see "Genetics: Glossary of terms", section on 'Gene editing'). A preclinical model using this approach was able to correct the sickle mutation in cultured bone marrow cells from patients with SCD, and cells manipulated in this manner could differentiate and restore hematopoiesis in a mouse model [81].

Anti-sickling beta globin gene — An artificial version of the beta globin gene has been developed that creates an amino acid substitution of glutamine for threonine at position 87 (beta globin T87Q) [73]. This amino acid switch replicates the region of the gamma globin sequence that is thought to block polymerization of sickle hemoglobin in the RBC.

Gene therapy with lovotibeglogene autotemcel (BB1111) has been used for SCD; this therapy consists of autologous HSCs and hematopoietic progenitor cells transduced with the lentiviral vector BB305 that expresses Hb AT87Q. Clinical experience includes the following:

In a 2017 case report, a 13-year-old boy with SCD who had multiple vaso-occlusive pain episodes and other SCD complications that were not improved with hydroxyurea or chronic transfusions was treated with an autologous HSCT in which his own hematopoietic stem cells were transduced with this construct and returned to him after myeloablative chemotherapy [82]. Following engraftment, he had increasing expression of the variant until it reached stable levels of approximately 50 percent of total hemoglobin at nine months, with a reciprocal decline in Hb S expression. He required no further analgesics, and had no vaso-occlusive events during the post-transplant observation period of more than 15 months. There were no major adverse events other than the expected cytotoxicity of the conditioning regimen.

In a 2021 report describing outcomes in 35 individuals who underwent autologous HSCT using this therapy with plerixafor-mobilized peripheral blood stem cells and myeloablative conditioning, all 35 had engraftment, with a median follow-up of 17.3 months (range, 3.7 to 37.6) [83]. The following post-transplant outcomes were reported:

Vaso-occlusive events decreased from a mean of 3.5 per year to a mean of 0.

Median hemoglobin increased from 8.5 g/dL to ≥11 g/dL.

Hb AT87Q accounted for ≥40 percent of hemoglobin and was present in 85 percent of RBCs.

Hb S decreased to approximately 50 percent.

Two patients developed anemia of unknown cause, without evidence of MDS.

There was one death, 20 months after transplant, in an individual with pulmonary hypertension, left ventricular hypertrophy, and cardiac interstitial fibrosis.

Gamma globin upregulation via targeting BCL11A — The gamma globin gene is the source of gamma chains (beta-like chains) for fetal hemoglobin (Hb F), the predominant hemoglobin expressed in late gestation and early infancy. It is a separate gene from beta globin and thus does not contain the sickle mutation (figure 1). (See "Structure and function of normal hemoglobins", section on 'Fetal hemoglobin'.)

The switch from gamma globin to beta globin expression leads to a reduction in Hb F and an increase in Hb A in early infancy. This switch is controlled in large part by the BCL11A gene, which encodes a transcriptional repressor of gamma globin expression. Manipulations that block the function of BCL11A reverse the switch and can dramatically increase the levels of Hb F, which in turn can lead to a major reduction in sickling and vaso-occlusive complications. Genetic manipulations have the potential to raise Hb F levels (and decrease Hb S) to a much greater extent than hydroxyurea.

Two studies from 2020 validated the approach of targeting BCL11A using RNA interference (RNAi) or gene editing:

RNAi – A study used RNAi from a lentiviral vector encoding a short hairpin RNA (shRNA) targeting BCL11A mRNA in six individuals [84]. The shRNA was embedded in a microRNA to promote erythroid-specific knockdown in autologous HSCs followed by autologous HSCT. Autologous HSCT using HSCs transfected with this construct and were followed for a median of 18 months. During 18 months of follow up, all six individuals had persistent high levels of Hb F production (Hb F, 20 to 42 percent; F cells, 59 to 94 percent) and there were no episodes of vaso-occlusive pain, acute chest syndrome, or stroke. One individual had two episodes of priapism.

Gene editing – A study in two individuals (one with SCD and one with beta thalassemia) used the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to disrupt BCL11A expression in autologous HSCs followed by autologous HSCT [85]. During approximately two years of follow up, both individuals had dramatic increases in Hb F (43 percent in the individual with SCD and >99 percent in the individual with thalassemia) and both experienced major reductions in their disease severity (no vaso-occlusive episodes and no need for transfusions).

Both studies documented transplant-related complications attributable to the myeloablative conditioning regimen. Additional studies using gene therapy or gene editing in SCD are under review (a fluid situation due to ongoing evaluations of patients initially treated in the early trials).

Details of BCL11A disruption and background information on Hb F expression, RNA interference, and gene editing are discussed separately [86]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'RNA interference' and "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing' and "Fetal hemoglobin (hemoglobin F) in health and disease".)

Delta globin gene — The delta globin gene is the source of beta globin-like chains for Hb A2, a minor adult hemoglobin that typically accounts for only 2 to 3 percent of total hemoglobin in children and adults. It is a separate gene from beta globin and thus does not contain the sickle mutation. Like Hb F, Hb A2 inhibits the polymerization of Hb S [87,88]. (See "Structure and function of normal hemoglobins", section on 'Hb A2'.)

Studies in transgenic SCD mice highlight the possible value of increasing delta globin gene expression [89,90].

Preclinical models using gene therapy to introduce the delta globin gene have not been reported, but patients with SCD who have especially high Hb A2 levels appear to have a milder clinical phenotype, suggesting that approaches to increase delta globin expression might be worthwhile [87].

Concern about myeloid malignancy in gene therapy studies — In early 2021, gene therapy studies using lentiviral vectors were suspended temporarily after 2 of 47 individuals with SCD who were participating in a study using the BB305 lentiviral vector subsequently developed myeloid malignancies (myelodysplastic syndrome [MDS] that later transformed to acute myeloid leukemia [AML] in one participant, AML in another participant) [91]. For the first participant, the investigative team concluded that MDS/AML was not related to the viral vector but was a result of the conditioning regimen [92]. Evaluation of the second patient, who had very limited engraftment of the modified HSCs and developed AML more than five years later, also determined that the gene therapy construct was unlikely to be responsible [93]. The insertion site was in a gene not known to be associated with oncogenesis and was present in most patients with SCD who received the same construct and did not develop AML, and several somatic mutations were present in the leukemic blasts unrelated to the vector but commonly seen in monosomy 7, which is known to complicate alkylating agent therapy. Low transgene expression, insufficient therapeutic response, and persistent hematopoietic stress may have contributed to somatic mutation evolution. Two other patients who were originally suspected of having MDS had transfusion-dependent anemia and trisomy 8, but there was no evidence of dysplasia or blasts on bone marrow evaluation [83,94].

Studies are indicated to assess for genetic risk factors for MDS and AML development after gene therapy for SCD. Hypotheses for the mechanism of leukemogenesis include insertional mutagenesis, transplant conditioning regimens, and expansion of preexisting premalignant clonal populations driven by regeneration of hematopoiesis with expansion of the autologous HSC population [95].

The optimal strategy to identify individuals with SCD who are at increased risk for transplant-related malignancy is unknown. Several strategies may be suggested but not proven to have clinical utility, such as clonal hematopoiesis screening prior to the procedure. The gene(s) and variant allele frequencies associated with an increased risk of MDS/AML following any curative therapy in SCD are unknown.

Individuals with thalassemia treated with the same lentiviral construct have not shown evidence of AML or MDS. However, no conclusive evidence exists to determine which features of disease or therapy predisposes to myeloid malignancy, from among myeloablative therapy, the lentiviral vector, SCD-related genetic predisposition, stress erythropoiesis, or some combination of these factors. MDS and AML have been observed in allogeneic transplant studies in SCD that did not involve gene therapy [69,70,96]. The cause(s) in individuals with SCD are under investigation.

Given that approximately 4 percent of participants in the gene therapy trial developed MDS/AML, coupled with the high rate of mortality, we are reluctant to advise children with severe SCD to pursue gene therapy or gene editing. While we recognize that others may have a different view, our hesitation for suggesting the relatively new gene therapy or editing trials to children is based on the following:

Multiple studies have demonstrated an expected median survival of 99 percent up to 18 years of age [9,10,57,97]. (See "Overview of the management and prognosis of sickle cell disease", section on 'Overall survival'.)

Experimental gene therapy and gene editing have not demonstrated a survival benefit equivalent to standard care.

Specific to children enrolled in clinical trials, 45 code of federal regulation § 46.405(b) requires the investigational agent must be at least as safe as standard care for greater than minimal risk research [11].

As more experience is gained regarding the adverse intermediate- and long-term therapy outcomes of gene therapy and gene editing trials, a parent or guardian can make an informed decision on behalf of their child as to the risk-benefit ratio.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: Sickle cell trait (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

Existing therapiesHydroxyurea, chronic transfusions, and new drugs approved by the US Food and Drug Administration (FDA) in 2017 to 2019 are effective at reducing vaso-occlusive pain and other complications of sickle cell disease (SCD). Indications are discussed in separate topic reviews. (See 'Timeline of drug development in SCD' above and "Hydroxyurea use in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Need for new therapies – Existing therapies require lifelong administration, do not eliminate vaso-occlusive complications, and may be challenging for some individuals to take. Transfusions carry several risks and burdens and often cannot be continued indefinitely. (See 'Limitations of available therapies' above.)

When to consider – Pharmacologic therapies may be explored as part of a well-conducted clinical trial if vaso-occlusive complications persist despite adequately administered hydroxyurea or other disease-modifying therapies or if these therapies cannot be used. Curative therapies may be considered in individuals with progressive vaso-occlusive complications despite FDA-approved therapies. For children, we reserve matched related donor hematopoietic stem cell transplant (HSCT) for those with preexisting stroke, silent cerebral infarcts, heart, lung, or kidney disease not responsive to disease-modifying therapy. For adults, we consider curative therapy if there is organ damage associated with an increased risk for early mortality, especially elevated tricuspid regurgitant velocity. (See 'When to consider investigational therapies' above and "Hematopoietic stem cell transplantation in sickle cell disease" and 'Therapies with curative intent' above.)

Pharmacologic approaches – Many new agents are being investigated, including drugs with the following effects (see 'Pharmacologic therapies' above):

Increasing fetal hemoglobin – (See 'Increasing Hb F' above.)

Reducing sickle hemoglobin polymerization – (See 'Reducing Hb S polymerization' above.)

Blocking sickle RBC or neutrophil interactions with the vasculature – (See 'Decreasing cell adhesion' above.)

Decreasing inflammation or oxidative stress – (See 'Decreasing inflammation' above and 'Decreasing oxidative stress' above.)

Reducing hemolysis – (See 'Decreasing hemolysis (hemopexin)' above.)

Combining approaches with different mechanisms might produce additive or synergistic effects.

Curative approaches – Curative approaches include allogeneic HSCT using an alternative donor or autologous HSCT using modified autologous hematopoietic stem cells (see 'Therapies with curative intent' above):

Alternative donor allogeneic HSCT – (See "Hematopoietic stem cell transplantation in sickle cell disease", section on 'Alternative donors'.)

Editing the beta globin gene – (See 'Beta globin gene correction' above.)

Adding an anti-sickling gene – (See 'Anti-sickling beta globin gene' above.)

Upregulating gamma globin expression to increase Hb F – (See 'Gamma globin upregulation via targeting BCL11A' above.)

Upregulating delta globin expression to increase Hb A2 – (See 'Delta globin gene' above.)

ACKNOWLEDGMENTS

We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The editorial staff at UpToDate would also like to acknowledge Griffin P Rodgers, MD, who contributed to earlier versions of this topic.

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Topic 110324 Version 36.0

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