مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
beta-thalassemia gene therapy
beta-thalassemia gene therapy
Farnaz Ameri,1,*
1. B.Sc. in Microbiology, Islamic Azad University of Shiraz, Iran
Introduction: Beta-thalassemia is an inherited disorder caused by reduced or absent β-globin chain production in hemoglobin, leading to severe anemia, ineffective erythropoiesis, and dependence on lifelong transfusions.Repeated transfusions result in iron overload, affecting the heart, liver, and endocrine glands, causing life-threatening complications.Current treatments include regular transfusions, iron chelation, and hematopoietic stem cell transplantation, the latter being curative but limited by donor availability, high costs, and immunological risks.These limitations have driven the development of gene therapy as a promising curative approach.
Methods: Recent advances in gene therapy aim to correct the underlying genetic defect or reactivate fetal hemoglobin (HbF).Main strategies include:Gene Addition via Lentiviral Vectors: Autologous hematopoietic stem cells (HSCs) are modified ex vivo with lentiviral vectors carrying a functional β-globin gene, then reinfused to reconstitute erythropoiesis.Genome Editing (ZFNs, TALENs, CRISPR-Cas9): Nuclease-based tools correct mutations or downregulate repressors such as BCL11A to reactivate HbF.CRISPR-Cas9, with higher efficiency and lower cost, is the most widely used.RNA-Based Approaches: Antisense oligonucleotides (ASOs) and engineered U7 snRNA correct abnormal splicing.HbF induction using drugs such as hydroxyurea, luspatercept, and sotatercept can also reduce disease severity.Additional strategies target ineffective erythropoiesis, iron overload, or excessive α-globin synthesis.
Results: Several therapies have reached advanced clinical testing:LentiGlobin BB305 (Zynteglo): Lentiviral-based therapy achieved transfusion independence in ~90% of transfusion-dependent β-thalassemia patients in phase 1/2/3 trials, regardless of genotype.FDA approved it in 2022 as the first gene therapy for thalassemia.CTX001 (Casgevy): CRISPR-Cas9–based therapy editing BCL11A binding sites in autologous HSCs achieved ≥12 months transfusion independence in 91% of patients in the CLIMB THAL-111 trial.FDA approval followed in 2023, marking the first CRISPR-based therapy.ZFNs (ST-400): Early-phase trials showed limited editing efficiency and modest HbF induction.TALENs: Demonstrated successful correction of β-globin mutations in induced pluripotent stem cells and animal models, restoring hemoglobin production with minimal off-target effects.Comparison:Lentiviral vectors offer durable expression and eliminate graft-versus-host disease risks, though rare concerns of insertional mutagenesis remain.CRISPR-Cas9 provides precise and cost-effective editing but raises concerns about off-target effects and long-term safety.RNA-based therapies allow reversible interventions but require repeated administration and are mutation-specific.
Conclusion: Gene therapy has revolutionized the therapeutic landscape for β-thalassemia, moving from supportive transfusions to curative genetic strategies.Lentiviral vector therapies (Zynteglo) and CRISPR-Cas9–based editing (Casgevy) demonstrate unprecedented clinical success, offering long-term transfusion independence and improved quality of life.However, unresolved challenges include potential off-target effects, insertional mutagenesis, high costs, and limited accessibility.Ongoing research is essential to refine gene delivery methods, ensure long-term safety, and expand affordability.With continued innovation, gene therapy is poised to become a global standard for curing β-thalassemia.