Gene Therapies for Sickle Cell Disease

Author: Kylie VanDerMolen 

Editors: Morgan McCullough and Michaela Price, PhD 

Today, we will be covering the landmark Food and Drug Administration (FDA)-approvals of the first gene therapies to treat sickle cell disease. On December 8, 2023, the FDA approved Casgevy (Vertex Pharmaceuticals Inc.), the first ever approval of a CRISPR-based genome editing therapeutic, and Lyfgenia (bluebird bio Inc.), a cell-based gene therapy, to treat sickle cell disease (SCD) in patients 12 years or older with vaso-occlusive events. In this post, we will introduce sickle cell disease and the available options for its treatment, discuss CRISPR/Cas9 gene editing and the mechanisms of action for Casgevy and Lyfgenia, and conclude with an overview of the clinical and economic impact of these approvals. 

Overview of Sickle Cell Disease

Sickle cell disease (or Sickle cell anemia) is a chronic and severe blood disorder that affects over 7 million people worldwide and approximately 100,000 people in the United States, with an increased prevalence among individuals of African descent.1 It has a high morbidity and mortality burden, especially in children, and a median life expectancy of only 43 years.1,2 The disease is characterized by abnormal red blood cells that cause obstructed blood flow throughout the body, leading to serious complications, including extremely painful episodes sometimes called “vaso-occlusive crises” or “pain crises”, chronic pain, stroke, and end-organ damage.3 The cause of the irregular blood cells, or “sickle cells” is an autosomal recessive genetic mutation in the β-globin chain of hemoglobin that causes production of hemoglobin S (HbS), an abnormal form of the adult hemoglobin protein (HbA). Under deoxygenation, HbS forms polymers that disrupt cell structure, leading to rigid, sticky, and deformed blood cells.4,5 

Figure 1. Overview of Sickle Cell Disease.
Sickle cell disease afflicts over 7 million people globally, decreasing lifespan and causing high mortality in children. The disease is caused by sickled red blood cells that can obstruct blood flow in blood vessels, causing severe complications. (Figure made by Kylie VanDerMolen.) 

Current Therapeutic Landscape

Figure 2. Therapeutic Landscape Prior to Casgevy and Lyfgenia. Existing treatment options for SCD include first-line treatment hydroxyurea (HU), L-glutamine, and crizanlizumab-tmca, which all reduce symptoms of SCD and the need for transfusions and hospitalization. L-glutamine and crizanlizumab can benefit the approximate 25% of SCD patients that do not respond to or tolerate hydroxyurea use, but these options are significantly more expensive than HU. Blood transfusions are commonly used to help with SCD symptoms; however, they are associated with their own set of risks. Blood and bone marrow stem cell transplantation is the only potentially curative option and is commonly used for children with complications, but it can be difficult to find an appropriate donor and is riskier in adults. (Figure made by Kylie VanDerMolen.) 

Prior to the two gene therapies approved in 2023, the FDA had approved four medicines for SCD. Hydroxyurea has long been the first-line treatment for SCD. Approved by the FDA for adults in 1998 and children in 2017 (Siklos, Addmedica), this oral medication reduces sickling of red blood cells and improves associated severe complications, including reduced pain crises, episodes of acute chest syndrome, need for transfusions and hospitalizations, and improved anemia.3,6 However, an estimated 25% of sickle cell patients do not respond to hydroxyurea or may have complications with adherence or adverse effects. 7 

The FDA approved L-glutamine in 2017 for patients 5 years and older (Endari, Emmaus Medical, Inc.) as an oral powder, which was shown to reduce sickle cell crises, incidence of acute chest syndrome, and hospitalizations.3 L-glutamine is a significantly more expensive therapeutic option than hydroxyurea, but it may be a good option for patients who do not tolerate hydroxyurea, as the two medications work via different mechanisms of action.8

Crizanlizumab-tmca, a monoclonal antibody administered intravenously, was approved for patients 16 years and older by the FDA in 2019 (ADAKVEO, Novartis), to decrease the occurrence of vaso-occlusive crises, the need for blood transfusions, and inflammation.3 It was found to be the most cost-effective for patients with a high frequency of vaso-occlusive crises (≥10 per year), but it is still significantly more expensive than hydroxyurea.7 Much of the study population in phase III studies for both L-glutamine and crizanlizumab also received concomitant hydroxyurea treatment due to its known benefits, with data supporting the use of combination therapy to minimize SCD symptoms when the first-line treatment is not enough.9

Lastly, the FDA granted accelerated approval to voxelotor for SCD patients over 12 years old in 2019 to prevent sickling of blood cells (Oxbryta, Global Blood Therapeutics). However, Pfizer withdrew it from the market upon determination of an unfavorable benefit-risk ratio in the approved population.3  

Aside from medications, patients with SCD also frequently undergo blood transfusions as a therapeutic intervention to provide more normal red blood cells to the bloodstream.3 Blood transfusions can help patients who do not respond to hydroxyurea, but they can be associated with adverse effects, such as iron overload (leading to organ damage), infections, and alloimmunization (when the patient’s immune system attacks the foreign blood).3,10 Blood and bone marrow stem cell transplants have been suggested to be the only available curative option for SCD, allowing for the production of normal red blood cells from a well-matched donor transplant.3 These are most commonly done in children who have had complications; however, less than 20% of SCD patients have an available matched sibling donor for this option. Transplants also incur greater risk in adults, can have severe adverse effects, and do not always cure chronic pain or repair prior damage.3,11 While many of the currently available treatments are effective in alleviating disease symptoms, there is an unmet need for a more comprehensive approach, especially for patients who do not respond well to treatment or who do not have an appropriate donor match for stem cell transplantation. 

CRISPR/Cas9 Gene Editing

Applications of gene-based therapies have been in development to better study and treat diseases caused by genetic mutations. Genome editing has emerged as a powerful and precise tool that has been refined to better enable its use in the clinical setting. In 2012, Nobel prize winning scientists Jennifer Doudna and Emmanuelle Charpentier discovered the ability to exploit the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) bacterial immune system to edit any DNA, including that of humans.12 For use in gene editing, the single guide RNA (sgRNA) makes a complex with the Cas9 enzyme and guides it to the target gene via complementary base pairing.13 Cas9 makes a double-stranded break (DSB) in the DNA that is then repaired using the host cell DNA repair machinery, which predominantly proceeds through the non-homologous end joining (NHEJ) pathway.13 NHEJ is inherently error-prone and can lead to small insertions or deletions in the target gene that disrupt the function of the protein it encodes.13 On the other hand, if a large amount of homologous DNA template containing a sequence of interest is added to the cell, the cell can use homology-directed repair (HDR) to repair the break and make a specific edit in a highly precise manner, such as restoring a mutation to its normal DNA sequence.13 CRISPR-based gene editing has been in development for the treatment of a number of diseases, including cancer, viral infections, and single-gene disorders like SCD.14 While very powerful, there are a number of challenges that have come with developing these therapeutic options, including immunoreactivity, off-target binding, safe delivery, and ethical considerations.14 Excitingly, the optimization of this technology over time has led to the development of a therapeutic option that demonstrates a favorable benefit-risk ratio in the clinic that granted the FDA approval of Casgevy.  

Mechanisms of Action

Both Casgevy and Lyfgenia are ex vivo gene therapies that utilize the patients’ own stem cells (CD34+ cells) from their blood, which are removed, edited, and infused back in via a single-dose hematopoietic stem cell transplant.15 Patients’ diseased cells are removed from their bone marrow with high-dose chemotherapy before the modified blood cells are replaced via Casgevy/Lyfgenia.15 Casgevy directly edits the DNA in patients’ CD34+ cells, where the CRISPR/Cas9 machinery is delivered via non-viral electroporation.16 The Cas9 complex targets the red blood cell-specific enhancer of the BCL11A gene, which encodes a transcription factor that suppresses transcription of the γ-globin genes after birth.17,18 γ-globin complexes with α-globin to make up the fetal version of hemoglobin (HbF), which has been found to inhibit polymerization of HbS by reducing its concentration.5,18 In Casgevy, the CRISPR/Cas9 machinery makes double-stranded breaks in the BCL11A gene that are repaired erroneously by NHEJ, effectively causing loss-of-function of the BCL11A transcription factor. In turn, γ-globin expression is re-activated in the patient when the cells are re-integrated, and the resultant increased level of HbF reduces red blood cell sickling.  

The mechanism of action for Lyfgenia is distinct from CRISPR/Cas9 gene editing. Lentiviral vectors remain the most popular gene delivery system for gene therapies in monogenic diseases.19 In Lyfgenia, the patients’ stem cells are transduced with a lentiviral vector that carries the sequence for the β-globin gene that encodes an amino acid substitution (T87Q).20 Once the cells are re-infused into the body, the modified sequence will be integrated into the host genome of the cell, and the cell will transcribe this modified gene to make βA-T87Q-globin.20 βA-T87Q-globin pairs with α-globin to make HbAT87Q, which functions similarly to normal HbA while reducing levels of HbS and sterically inhibiting HbS polymerization to reduce red blood cell sickling.20  

There are risks associated with both methods of gene delivery. Lentiviruses preferentially integrate into regions of active transcription in the genome, leaving a risk for insertion into places in the genome that may inappropriately alter transcription of important genes, such as silencing tumor suppressor genes or activating proto-oncogenes that then lead to the development of cancer.19 Several measures have been taken to optimize and improve safety of lentiviral vector use in the clinical setting.19 In contrast, CRISPR/Cas9 edits the genome in a precise manner and can be delivered via a non-viral method, but the risk of off-target editing remains. These complications have not been observed thus far with the use of either therapy.17 

Figure 3. Mechanisms of action for Lyfgenia and Casgevy. (1) Both treatments begin with stem cell removal from the blood marrow. (2) Ex vivo gene editing is done in the stem cells via lentiviral vector transduction (Lyfgenia) or CRISPR/Cas9 gene editing, delivered by electroporation (Casgevy). (3) After editing, the modified cells are re-infused into the patient’s bone marrow. Patients undergo chemotherapy prior to re-infusion to remove existing cells first. (4) Lyfgenia treatment results in integration of the modified β-globin gene, βA-T87Q-globin, into the genome where it is expressed in vivo to make HbAT87Q. Casgevy editing leads to erroneous repair by NHEJ in the BCL11A gene, which disrupts the ability of BCL11A to act as a transcriptional repressor of the γ-globin gene. This leads to increased HbF production. (5) Both mechanisms lead to decreased red blood cell sickling by reducing HbS and inhibiting its polymerization. (Figure made by Kylie VanDerMolen.) 

Clinical and Economic Significance

These innovative gene therapies hold substantial power to cure SCD, and the first approval of CRISPR/Cas9 for clinical use is monumental as a precedent for the continued treatment of diseases with genetic causes. As of March 2024, there are clinical trials utilizing CRISPR technology in 9 different disease areas, including two phase 1/2 trials to treat SCD with promising efficacy and safety data and one currently enrolling for a phase 1 trial. 21 

As of August 2024, bluebird bio has started cell collection on four patients for Lyfgenia treatment in the U.S., and as of November 2024, Vertex Pharmaceuticals has started cell collection on 40 patients for Casgevy worldwide.22,23 Bluebird has 70 qualified treatment centers for administration of the therapeutic, and Vertex has 45 treatment centers with a goal of 75 and an estimated global patient pool of 58,000. 22,23 

Logistically and financially, the use of these gene therapies is still complicated. Access to facilities with the appropriate technology to administer the treatment is limited, and treatment is estimated to cost around $2-3 million per patient.21,24 However, this is approximately consistent with the cost of lifetime treatment for SCD, which was estimated at $1.7 million in 2022 with about $44,000 of out-of-pocket costs for non-elderly patients.25 In 2016, the total economic burden for SCD patients was $811 million in the United States.25 An estimated 50-60% of SCD patients are on Medicaid, and the projected cost to provide gene therapy treatment to all Medicaid-insured patients with severe SCD in 10 states is $5.5 billion, which presents a significant challenge to affordability.24,25 Bluebird reported progress toward accessible treatment, stating that more than half of Medicaid-insured SCD patients in the U.S. are in states that have affirmed Lyfgenia coverage, and nearly 20% are in states that have already authorized approval for treatment for at least one resident.22 To reduce barriers to accessing these treatments, the Centers for Medicare and Medicaid Services (CMS) has developed the Cell and Gene Therapy (CGT) Access Model, through which the federal government will negotiate lower prices for treatment with Vertex and bluebird on behalf of state Medicaid agencies.24 Continued efforts to improve these genome editing therapies are driven by a push for minimizing costs while improving safety and experience, which will be key for overall reduction of lifetime medical costs and economic burden of SCD on patients and payers.21  

Not only are SCD gene therapies costly, but their development is also expensive. High costs of clinical trials and financial pressures from investors have led to layoffs in companies focused on CRISPR-based gene therapies.21 There is acknowledgement of a need for change in regulatory approaches to improve development of these therapeutics, especially for rare diseases. One solution in development for CRISPR therapies is platform technology, where all components of a treatment are packaged together, and changes are made per disease in order to reduce regulatory burden and streamline drug development.21 The U.S. Congress passed the Food and Drug Omnibus Reform Act (FDORA) in 2022, which includes the Platform Technology Designation Program to facilitate this development.26 The balance between innovative medicine and affordability presents a constant challenge, but the overall societal benefit for curative therapies continues to drive the development of breakthrough drugs, such as Casgevy and Lyfgenia. 

References

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