Sickle Cell Disease Treatment: From Hydroxyurea to FDA-Approved Gene Therapy

Research-informed explainer — last updated April 12, 2026

Sickle cell disease (SCD) treatment has entered a new era: in December 2023, the FDA approved the first two gene therapies for SCD — one that adds a functional beta-globin gene and one that reactivates fetal hemoglobin — offering, for the first time, the possibility of a functional cure without a matched donor. These options coexist with hydroxyurea, the decades-old standard that remains widely underutilized despite strong evidence of benefit.

This article draws on research from four specialists whose published work addresses the evidence behind existing treatments and the biology that makes SCD uniquely complex. Brian Adler, MD, at Brookwood Baptist Medical Center in Birmingham, contributed to the MSH (Multicenter Study of Hydroxyurea) long-term follow-up published in JAMA in 2003 (890 citations) showing that hydroxyurea reduced mortality and acute chest syndrome in adults, and published on the nitric oxide vascular mechanisms that underlie SCD complications (383 citations). Nigel Key, MD, Harold R. Roberts Distinguished Professor at UNC, published on the role of the extrinsic coagulation pathway in thrombosis (703 citations) — explaining why clotting complications in SCD are mechanistically distinct and clinically challenging. Adam Cuker, MD, Section Chief of Hematology and Director of the Penn Comprehensive Hemophilia and Thrombosis Program, co-authored the ASH 2020 VTE guidelines (1,356 citations) and published on hemophilia B gene therapy (739 citations), providing relevant context on both the anticoagulation challenges in SCD and the gene therapy technology now applied to the disease. Kehinde Adekola, MD, at Northwestern Memorial Hospital, published directly on real-world hydroxyurea effectiveness and safety in SCD patients (34 citations) and barriers to its use (29 citations) — grounding the article in the access and adherence challenges that affect SCD patients in practice.

What is sickle cell disease?

SCD is caused by a single point mutation in the beta-globin gene (HBB), converting glutamic acid to valine at position 6 of the beta-globin protein. This produces hemoglobin S (HbS), which polymerizes when deoxygenated, deforming red blood cells into the rigid, crescent-shaped "sickle" form. Sickled cells obstruct small blood vessels (vaso-occlusion), causing the painful crises, organ damage, and strokes that define the clinical picture of SCD.

SCD occurs most commonly in patients who inherit two copies of the sickle mutation (HbSS, sickle cell anemia), but also in those with one sickle and one other abnormal beta-globin variant (HbSC, HbS-beta thalassemia). HbSS typically produces the most severe disease.

Hydroxyurea: the evidence-based cornerstone

Hydroxyurea (hydroxycarbamide) was the first FDA-approved disease-modifying therapy for SCD, approved in 1998 for adults with three or more vaso-occlusive crises per year, and later for children. It works primarily by increasing fetal hemoglobin (HbF) production — HbF inhibits HbS polymerization and keeps red cells flexible. It also reduces white cell and platelet counts, decreasing the inflammatory adhesion events that trigger vaso-occlusion.

The MSH trial follow-up published in JAMA in 2003, contributed to by Dr. Adler (890 citations), enrolled adult patients with frequent painful crises and followed them for a median of 9 years. Patients taking hydroxyurea had significantly lower mortality (relative risk approximately 0.6), lower rates of acute chest syndrome (the most common serious pulmonary complication), and fewer transfusions. Survival was directly correlated with achieved HbF levels.

Despite this evidence, Dr. Adekola's real-world studies — examining both effectiveness in children (34 citations) and barriers to prescribing (29 citations) — highlight that hydroxyurea remains underutilized, particularly outside major academic centers. In a cohort of SCD children in Nigeria, hydroxyurea reduced crisis frequency from 50% to 2.7% over 12 months, and the primary barriers identified were provider knowledge gaps and concerns about long-term safety. Similar access disparities exist in the United States, particularly in adult care settings.

Newer non-gene therapy disease-modifying agents

Three additional FDA-approved drugs target different mechanisms of SCD pathophysiology:

Voxelotor (Oxbryta): Approved in 2019, voxelotor directly inhibits HbS polymerization by binding hemoglobin and stabilizing its oxygenated form. In the HOPE trial, 51% of voxelotor-treated patients achieved a greater than 1 g/dL hemoglobin increase versus 7% on placebo, with significant reduction in hemolysis markers.

Crizanlizumab (Adakveo): Approved in 2019, crizanlizumab blocks P-selectin, a cell adhesion molecule that mediates the interaction between sickled red cells, white cells, and endothelium. In the SUSTAIN trial, crizanlizumab reduced annual crisis rate by 45% compared to placebo.

L-glutamine (Endari): Approved in 2017, reduces oxidative stress and was shown to reduce the rate of acute crises and hospitalizations.

These agents are generally used in patients who have persistent crises despite hydroxyurea, or who cannot tolerate hydroxyurea. They address specific pathways but do not change the underlying hemoglobin.

Stem cell transplant: the established curative approach

Allogeneic stem cell transplant from an HLA-matched sibling donor is the only established curative approach for SCD and has been performed since the 1980s. Event-free survival rates of 80–85% have been reported in children with matched sibling donors who undergo transplant before developing significant organ damage. However, only about 15–20% of SCD patients have a fully matched sibling donor, limiting access dramatically.

Haploidentical transplant (using a half-matched family member) has expanded donor availability, and reduced-intensity conditioning protocols have extended feasibility to older patients and those with organ dysfunction. The key tradeoff is transplant-related mortality and GVHD risk versus disease control.

Gene therapy: the new curative frontier

Two gene therapies received FDA approval in December 2023 for patients 12 and older with SCD and recurrent vaso-occlusive crises.

Betibeglogene spartacus (Zynteglo): A lentiviral vector delivers a modified beta-globin gene into the patient's own hematopoietic stem cells. The HGB-206 and HGB-210 trials showed that approximately 88% of patients achieved transfusion independence, with the modified anti-sickling hemoglobin making up a substantial fraction of total hemoglobin. The procedure involves stem cell collection from the patient, gene modification in a laboratory, myeloablative conditioning chemotherapy (busulfan), and reinfusion.

Exagamglogene autotemcel (Casgevy): Uses CRISPR-Cas9 to disrupt the BCL11A gene, which normally suppresses fetal hemoglobin production. Disrupting BCL11A reactivates HbF. In the CLIMB-SCD-121 trial, 28 of 29 patients (97%) were free of severe vaso-occlusive crises for at least 12 consecutive months after treatment.

Dr. Cuker's published work on gene therapy for hemophilia B (739 citations) — where a functional factor IX gene was delivered by an AAV vector, eliminating bleeding episodes in 10 patients — provides relevant context on the maturity and durability of gene therapy approaches for inherited blood disorders, though the SCD gene therapies use different vector technologies.

Who qualifies for gene therapy?

Both gene therapies are approved for patients aged 12 and older with SCD and a history of two or more vaso-occlusive crises per year in the past two years. Because both require myeloablative chemotherapy conditioning, they are not appropriate for patients with severely compromised organ function. The manufacturing process takes several months, and patients typically require bridging therapy during this period.

Cost and access remain significant barriers: gene therapies for SCD carry list prices in the range of $2–3 million per patient. Coverage determinations are evolving, and advocacy and assistance programs through manufacturers exist for qualifying patients.

Questions to ask your doctor

• Am I on the right dose of hydroxyurea, and is my HbF level being monitored to confirm it is working?
• If hydroxyurea is not controlling my crises adequately, which of the newer agents — voxelotor or crizanlizumab — might be appropriate to add?
• Do I have a matched sibling donor, and should I be evaluated for allogeneic stem cell transplant?
• Do I meet the criteria for one of the approved gene therapies, and what is involved in the evaluation process?
• What regular monitoring should I be receiving for SCD-related organ complications — cardiac, pulmonary, renal, and eye?
• Are there SCD clinical trials open at a center near me?

The bottom line

SCD treatment has expanded from a single drug (hydroxyurea) to a menu of disease-modifying agents and, now, two FDA-approved gene therapies that offer the prospect of a functional cure for appropriately selected patients. Hydroxyurea remains the most widely applicable first-line disease-modifying therapy, proven to reduce mortality and serious complications, yet it continues to be underutilized. For patients who are not well controlled on existing therapies, gene therapy evaluation at a specialized center is now a realistic option.