Beta Late Than Never
Beta thalassemia is a genetic blood disorder that affects the production of hemoglobin, a protein in red blood cells that carries oxygen throughout the body. Individuals with beta thalassemia have a deficiency in beta globin, a subunit of hemoglobin, resulting in decreased oxygen-carrying capacity and anemia. The severity of beta thalassemia can vary from mild to severe, and individuals with the severe form require lifelong blood transfusions and iron chelation therapy to manage the condition.
Adult hemoglobin (HbA) consists of four polypeptides, two alpha chains and two beta chains, which associate to form a larger quaternary structure. These polypeptides are encoded by three different genetic loci: HBA1, HBA2, HBB. The HBA1 and HBA2 loci are located on chromosome 16 and encode for nearly identical alpha globin chains, and the beta chains are encoded by the HBB locus located on chromosome 11. Mutations in the HBB locus are responsible for causing beta thalassemia and can be inherited; specific mutations vary depending on the specific population. Common mutations include BO-Thalassemia, which completely eliminates the production of beta globin chains due to a splice site mutation, and B+-Thalassemia, where a common C to T mutation results in reduced production of the beta globin chains.
Figure 1. Cartoon representation of adult hemoglobin.
Ready, Set, Zynteglo
Gene therapy is a promising candidate being used to treat and manage beta thalassemia. Zynteglo, a gene therapy for beta thalassemia, was approved for use in the European Union in 2019 and in the United States in 2022. The process for treatment with Zynteglo is unlike most medications which are directly administered to patients. First, the patient’s own blood stem cells are collected, then shipped to a Zynteglo manufacturing facility. The cells are then transduced with Zynteglo, a lentiviral vector that incorporates a modified version of beta globin into the cell’s genome and results in expression of functional beta globin in the patient’s own blood stem cells. This process can take between 70 and 90 days to ensure enough cells are successfully transduced with the vector and that they pass the appropriate quality control standards.
Before the Zynteglo-treated cells are re-administered to the patient, they must first undergo a round of chemotherapy to eliminate their bone marrow cells that contain the loss-of-function copy of the gene. Following chemotherapy, the patient receives their Zynteglo-treated cells through bone marrow transplant, resulting in a one-time treatment for beta thalassemia. The transplanted cells will continue to proliferate and differentiate, supplying the patient with a lifetime supply of healthy blood cells.
The phase 3 clinical trials for Zynteglo assessed the safety and outcomes of the treatment including transfusion independence, measurement of total blood hemoglobin, and iron reduction. Overall, the phase 3 trial was wildly successful with 91% of patients achieving complete transfusion independence and near normal hemoglobin levels with these results lasting up to 39 months as of last reporting with the duration continuing to grow. A majority of the patients were also able to completely stop iron chelation therapy. Together, these results demonstrate the promise of Zynteglo as a treatment for beta-thalassemia and for the field of gene therapy.
Enhance and Optimize
In beta-thalassemia, the mutations in the HBB gene lead to reduced or absent beta-globin production, which disrupts the balance of alpha- and beta-globin chains in hemoglobin. This imbalance causes the alpha-globin chains to form aggregates or "globin polymerization," leading to premature destruction of red blood cells, anemia, and other complications. The introduction of a wild-type HBB gene is not always sufficient to alter the balance of the chains. Zynteglo has been engineered to include a point mutation of the HBB gene, T87Q, which antagonizes globin polymerization without affecting its oxygen-carrying capacity, resulting in restoration of normal functional cells.
Another key feature of Zynteglo that makes it an effective therapeutic is its proprietary BBV305 LVV promoter that controls expression of the transgene. This non-viral promoter allows for gene-specific expression in cells of the erythroid lineage. This added layer of design allows for gene expression only in red blood cells and their precursors. The choice of a lineage-specific promoter is often key in the designs of gene therapies that target a subset of cells.
The cost of Zynteglo is reported to be around $2.8 million per patient. This high cost has sparked debates around the world about the affordability and accessibility of gene therapy treatments, as well as the ethical implications of pricing life-saving treatments beyond the reach of most patients. Bluebird Bio has defended the price, stating that it reflects the long-term value of a one-time treatment that can potentially cure a lifelong condition, as well as the high costs associated with research and development. For example, patients receiving routine blood transfusions and medications can have healthcare costs totaling an average of $127,000/year. Nonetheless, the cost of Zynteglo remains a significant hurdle for patients and healthcare systems.
Besides gene replacement, other strategies are being explored for gene therapy to treat beta thalassemia. These strategies aim to address the underlying genetic defect or enhance the production of functional beta globin chains. CRISPR/Cas9 gene editing has been investigated to directly correct mutations to the HBB gene, and this approach is advantageous because it does not involve lentiviral integration of a foreign gene cassette. However, as a variety of mutations exist that can cause the disease, this treatment would need to be tailored at a patient-specific level.
Besides trying to directly correct the disease-causing mutations with CRISPR/Cas9, alternative approaches which attempt to reactivate production of fetal hemoglobin have also been investigated in the clinic. Fetal hemoglobin is produced from the first six weeks of pregnancy to the first six months of postnatal life followed by a rapid decrease in production. The genes HBG1 and HBG2 code for the hemoglobin gamma chains which replace the beta chains in fetal hemoglobin and these genes are repressed by BCL11A, a transcriptional repressor. CTX001 is a gene therapy in which CRISPR/Cas9 edits an enhancer that regulates this transcriptional repressor of fetal hemoglobin in patient-derived stem cells. This therapy has also shown promise in early clinical trials with high levels of specific editing and increased production of fetal hemoglobin as well as transfusion independence.
Beta thalassemia is a monogenic disorder that results in decreased production of hemoglobin and generally requires continual blood transfusions and iron chelation therapies to manage. Gene therapy to treat beta thalassemia is currently approved for use and new methods for treating the disease are currently being investigated. Overall, these therapies have the potential to drastically increase quality of life for people suffering with the disease, however, due to pricing concerns the future of its widespread adoptions remains unknown.
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