Exploring the breakthrough gene therapies for sickle cell disease, their mechanisms, evidence, and implementation challenges
Americans with SCD
Patients free from crises after Casgevy
First CRISPR therapy approved
Cost per treatment
"I would wake up in pain most days. Every day, before I put my feet on the floor, I'd reach into my nightstand for medicine."
For KeAndra Hickman, diagnosed with sickle cell disease at birth, life was measured in pain crises. "I would wake up in pain most days," she recalls. "Every day, before I put my feet on the floor, I'd reach into my nightstand for medicine." 2 Her experience reflects the reality for approximately 100,000 Americans and millions worldwide living with this inherited blood disorder. 1 2 Then, in 2022, she received an experimental treatment—a half-matched bone marrow transplant. The results were transformative. "I'm now living a life that previous doctors said I never would," says Hickman. 2
Stories like KeAndra's are becoming increasingly common as groundbreaking gene therapies emerge from laboratories and enter clinics. In late 2023, the field reached a historic milestone: the first-ever approval of CRISPR-based medicine, Casgevy, for treating sickle cell disease and transfusion-dependent beta thalassemia. 3 This article explores whether we have truly reached the tipping point where these transformative treatments can and should be widely implemented, examining the science behind them, their remarkable results, and the challenges that remain in making them accessible to all.
Sickle cell disease (SCD) is an inherited genetic disorder caused by a single point mutation in the β-globin gene (HBB). 5 6 This tiny error—a change in just one of the three billion letters of the human genetic code—has devastating consequences. The mutation causes hemoglobin, the oxygen-carrying protein in red blood cells, to behave abnormally, transforming these normally flexible, disc-shaped cells into fragile, crescent-shaped "sickles." 3 5
These misshapen cells are more than just dysfunctional—they're destructive. They clump together, blocking blood flow in small vessels throughout the body.
The disease disproportionately affects people of African, Caribbean, Middle Eastern, and South Asian descent, making it not just a medical issue but one of health equity. 2 For decades, treatments have focused primarily on managing symptoms rather than addressing the root cause. That is, until now.
Gene therapy represents a fundamental shift from managing symptoms to addressing the genetic root cause of sickle cell disease. Currently, two main approaches have shown remarkable success, both involving modifying a patient's own cells.
Casgevy, the first-ever approved CRISPR-based medicine, takes an ingenious approach sometimes called "nature's reverse." Instead of fixing the defective hemoglobin gene directly, it targets a different genetic pathway. 3 5
Blood-forming stem cells are collected from the patient
In the laboratory, the CRISPR-Cas9 system is used to precisely edit these cells, knocking out the BCL11A gene—a genetic switch that normally turns off fetal hemoglobin production after birth 3 5
The patient receives chemotherapy to make space in the bone marrow
The genetically edited cells are infused back into the patient
The edited cells engraft in the bone marrow and begin producing red blood cells with elevated fetal hemoglobin 3
This fetal hemoglobin is key—it doesn't sickle, and when present in sufficient quantities, it prevents the sickling of red blood cells containing the defective adult hemoglobin. 5 The result? A one-time treatment that addresses the underlying cause of sickling.
The second approved gene therapy, Lyfgenia, uses a different strategy. It employs a modified virus (lentivector) to deliver a functional hemoglobin gene into the patient's stem cells. 3 This added gene produces hemoglobin that functions normally, compensating for the defective sickle hemoglobin.
| Therapy | Mechanism | Efficacy | Approval Status |
|---|---|---|---|
| Casgevy (exa-cel) | CRISPR editing of BCL11A to increase fetal hemoglobin | 93% of patients free from vaso-occlusive crises for ≥12 months 3 | FDA-approved (Dec 2023) 1 |
| Lyfgenia | Lentiviral vector adding functional hemoglobin gene | 94% free from severe vaso-occlusive events (6-18 months post-infusion) 3 | FDA-approved (Dec 2023) 3 |
| Reni-cel (EDIT-301) | CRISPR/Cas12a editing of gamma globin promoters | 27 of 28 patients free of vaso-occlusive events post-infusion 3 | In clinical trials |
| BEAM-101 | Base editing of HBG1/2 promoter regions | Robust increases in fetal hemoglobin in clinical trials 3 | In clinical trials |
While the ability of gene therapy to reduce pain crises has been well-documented, some of the most compelling evidence for its transformative potential comes from a recent study examining its effect on brain blood flow.
Researchers at St. Jude Children's Research Hospital conducted a detailed investigation into how gene therapy affects cerebral hemodynamics—blood flow in the brain. 7 They recognized that many sickle cell patients experience increased blood flow speed in the brain as the body attempts to compensate for reduced oxygen delivery by sickled cells.
The findings, published in the American Journal of Hematology in June 2025, were striking. All three patients showed significant improvement in brain blood flow after receiving gene therapy. The elevated blood flow speed—a known risk factor for stroke—decreased anywhere from 22% to 43%, reaching mostly normal levels that remained stable over time. 7
"You can think of red blood cells filled with oxygen like a bus filled with people. If the bus is going too fast, passengers can't get off the bus, and oxygen is not delivered. However, if the bus slows down... then oxygen gets properly delivered to the brain tissues."
| Domain of Life | Improvement Measure | Patient Group | Significance |
|---|---|---|---|
| Social Functioning | +16.5 point improvement on ASCQ-Me scale 1 | Adults with SCD | Exceeded minimal clinically important difference threshold 1 |
| School Functioning | +45 point improvement on PedsQL scale 1 | Adolescents with SCD | Surpassed population norms 1 |
| Emotional Well-being | +8.5 point improvement on ASCQ-Me scale 1 | Adults with SCD | Clinically meaningful improvement 1 |
| Overall Health | 14.0 point improvement on EQ-5D-5L scale (from baseline 82.2) 1 | Adults with beta thalassemia | Surpassed thresholds for minimal clinically important difference 1 |
Despite the exciting scientific advances, significant challenges remain in implementing these therapies widely. As Dr. Josu de la Fuente noted, "Although exa-cel is a complex and costly treatment, the significant improvements in quality of life shown in these studies make it a worthwhile investment." 1 The question is whether our healthcare systems are ready to make that investment.
The most prominent barrier is staggering cost. Gene therapies for sickle cell disease can cost as much as $3.1 million for the gene therapy drug alone, creating significant access barriers, particularly for the Medicaid population that comprises many sickle cell patients. 9
There are also complex treatment requirements. The process requires extended hospital stays, specialized care teams, and complex logistics that are currently only available at limited specialized centers. 9 The preparatory chemotherapy adds significant burden and risk, particularly for patients who already have organ damage from their disease. 5
Recognizing these challenges, the Centers for Medicare & Medicaid Services (CMS) launched the Gene and Cell Therapy Access Model in January 2024. This initiative brings together CMS, state Medicaid agencies, and pharmaceutical companies to negotiate outcomes-based payment agreements. As of July 2025, 33 states and the District of Columbia have indicated they will participate. 9
Participating in CMS Gene Therapy Access Model
Approved for Casgevy use in the UK
The National Health Service (NHS) in the U.K. has also taken steps to improve access, approving Casgevy for use at specialist NHS centres, though initially for approximately 50 people per year. 5
The evidence is compelling: gene therapy for sickle cell disease has transformed from a distant dream to a clinical reality. The robust data from multiple studies—showing elimination of pain crises, normalization of brain blood flow, and dramatic improvements in quality of life—suggest that yes, the time for implementation has come.
"Patients are returning to school, back to work, and overall spending more time with their families and less time in the hospital. It's a powerful example of how clinical research drives real-world impact."
However, implementation must be accompanied by concerted efforts to address cost barriers and expand access. The challenge now is not scientific but systemic: creating equitable access to these transformative treatments.
The future is bright. With continued research into more accessible genetic targets like FLT1 4 , the development of oral therapies that might mimic the effects of gene editing 5 , and the refinement of delivery techniques, the next generation of treatments may be even more effective and accessible.
For KeAndra Hickman and Kyle—another patient who can now pursue his dream of becoming a pilot thanks to gene therapy 9 —the transformation has already occurred. The task before us is to ensure that every patient with sickle cell disease has the same opportunity for a cure. The science has delivered; now our healthcare systems must rise to the challenge.