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Gene therapy: A promising approach for hereditary haemoglobinopathies

Presented by
Dr Haydar Frangoul, Sarah Cannon Research Institute, USA
EHA 2021
Gene addition and gene editing approaches for sickle cell disease (SCD) and transfusion-dependent β-thalassaemia (TDT) have shown encouraging results in clinical studies. Long-term follow-up will be required to assess the long-term safety and durability of gene expression.

Dr Haydar Frangoul (Sarah Cannon Research Institute, USA) presented gene therapy approaches for 2 haemoglobinopathies caused by mutations: SCD and TDT [1]. SCD is an inherited disorder of haemoglobin affecting 270,000 infants born yearly worldwide, leading to chronic haemolysis and vaso-occlusive crises (VOCs). Patients with SCD have a lower life expectancy (median 48 years) [2]. Current therapy includes supportive care, transfusion, and biologicals. Allogeneic stem cell transplantation is the only curative therapy; however, most of the patients lack an HLA-identical donor. β-thalassaemia affects 40,000 infants born each year, approximately half of them being classified as transfusion-dependent. Patients suffer from iron overload, thrombosis, skeletal, and cardiopulmonary symptoms. Current therapy includes red blood cell transfusions, iron chelation therapy, and luspatercept. Allogeneic bone marrow transplant from HLA-identical siblings is the only curative therapy.

There are 2 approaches to gene therapy: gene editing and gene addition [1]. An example of gene addition in haemoglobinopathies is a lentiviral vector encoding a modified β-globin gene including an anti-sickling mutation. Dr Frangoul presented 2 case reports, with both patients expressing ≤50% of the transduced β-globin after >1-year post-treatment [3,4]. In a phase 1/2 study (NCT02140554) including 32 patients with SCD, LentiGlobin treatment effectively prevented vaso-occlusive events [5].

Dr Frangoul also presented a gene-editing approach to increase foetal haemoglobin (HbF) production. In patients with SCD and TDT, symptoms occur when haemoglobin is switched from foetal to adult. In patients with persistence of HbF, fewer or no symptoms of SCD or TDT are present, suggesting HbF could be a treatment option. A CRISPR-Cas9 gene-editing tool (CTX001) was used to target BCL11A to decrease the expression of BCL11A protein and increase the expression of HbF [6]. Patients’ blood stem cells were collected and CRISPR-Cas9-edited. Patients received chemotherapy to facilitate engraftment, infused with CTX001 and followed up for Hb production, HbF expression, transfusion requirements (TDT; NCT03655678), and VOCs (SCD; NCT03745287).

Preliminary results of the first 7 TDT patients in this study showed a clinically meaningful expression of HbF. Increased total haemoglobin was achieved early and maintained, and all patients became transfusion independent (median follow-up 8.9 months). CTX001 was also used in 3 SCD patients and the first results after a median follow-up period of 7.8 months were presented at the EHA 2021 Virtual Congress. HbF represented 31–47% after 3 months with a trend towards an increase at later time points. A pancellular HbF expression of almost 100% was observed with follow-up times ≥4 months. All patients had detectable haptoglobin and improved LDH, indicating no evidence of haemolysis, and were VOC-free. All patients treated to date demonstrated increased total haemoglobin and HbF [7].

Despite encouraging results, gene therapy approaches still have limitations. Recently, cases of myelodysplastic syndrome and acute myeloid leukaemia after receiving LentiGlobin were reported (NCT02140554; NCT04293185). Follow-up times are still short and there is a need for high-dose chemotherapy to facilitate engraftment.

Dr Frangoul concluded that “gene therapy approaches can offer an alternative to allogeneic stem cell transplantation especially for patients who lack an HLA-identical donor.” Data for gene addition and gene editing approaches are promising. Additional follow-up is required to determine the long-term safety and persistence of gene-modified cells in the marrow.

    1. Frangoul H. Gene therapy approaches to treatment of haemoglobinopathies. P210-1, EHA 2021 Virtual Congress, 9–17 June.
    2. DeBaun MR, et al. Blood 2019;133(6):615–7.
    3. Cavazzana-Calvo M, et al. Nature 2010;467(7313):313–22.
    4. Ribeil JA, et al. N Engl J Med 2017;376(9):848–55.
    5. Kanter J, et al. Abstract 365, ASH 2020, 7–10 December.
    6. Frangoul H, et al. N Engl J Med 2021;384(3):252–60.
    7. Grupp S, et al. EP736, EHA 2021 Virtual Congress, 9–17 June.


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