Gene Therapy of the Hemoglobinopathies

Abstract

Sickle cell disease and the ß-thalassemias are caused by mutations of the ß-globin gene and represent the most frequent single gene disorders worldwide. Even in European countries with a previous low frequency of these conditions the prevalence has substantially increased following large scale migration from Africa and the Middle East to Europe. The hemoglobin diseases severely limit both, life expectancy and quality of life and require either life-long supportive therapy if cure cannot be achieved by allogeneic stem cell transplantation. Strategies for ex vivo gene therapy aiming at either re-establishing normal ß-globin chain synthesis or at re-activating fetal γ-globin chain and HbF expression are currently in clinical development. The European Medicine Agency (EMA) conditionally licensed gene addition therapy based on lentiviral transduction of hematopoietic stem cells in 2019 for a selected group of patients with transfusion dependent non-ß° thalassemia major without a suitable stem cell donor. Gene therapy thus offers a relevant chance to this group of patients for whom cure has previously not been on the horizon. In this review, we discuss the potential and the challenges of gene addition and gene editing strategies for the hemoglobin diseases.

Improving outcomes and quality of life for patients with transfusion-dependent β-thalassemia: recommendations for best clinical practice and the use of novel treatment strategies

“…The transduced stem cells are then reinfused into the patient where the modified cells replicate, repopulate the blood compartment, and facilitate normal hemoglobin synthesis (Figure 2). [73,74] The first gene therapy, betibeglogene autotemcel (beti-cel; bluebird bio), is currently in clinical trials in the USA for patients with TD β-thalassemia aged ≤ 50 years for whom HSCT is appropriate but no HLA-matched donor is available. Beti-cel is a genetically modified autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with a lentiviral vector encoding the β A-T87Q -globin gene [75].…”

Genome-based therapeutic interventions for β-type hemoglobinopathies

“…Retroviral vectors have been used for over 20 years for in vivo and ex vivo gene therapies with significant advantages such as the long-term and stable transgene expression into the host genome, owing to their ability to infect only dividing cells (hematopoietic stem cells). On the other hand, the permanent integration of the vector genome into the host genome can pose additional risks and, in particular, there is a possibility of triggering cellular oncogenesis, as the transgenic material is randomly integrated, which can lead to the development of malignancies [ 115 , 127 , 128 ]. Later, the development of self-inactivating retroviral vectors was a major step forward to reduce the aforementioned risks, at least in theory; however, the integration mechanisms of retroviruses remain quite where they usually lead to sub-therapeutic levels, in terms of efficiency.…”

“…Based on the latest report for active gene therapy clinical trials, 35 out of 50 transfusion-dependent thalassemia patients, between ages 5 and 64 years old, were successfully treated, and in most patients, the transfusion was reduced or discontinued. The majority of the patients did not show any severe adverse events in relation to vector integration and gene therapy conditions [ 128 , 164 ]. In 2018, among the aforementioned patients, a new protocol was designed where the transduction has been made in CD34 + cells, using a new vector called GLOBE, and then administered by intraosseous infusion to the posterior-superior iliac crests.…”

Luspatercept for β-thalassemia: beyond red blood cell transfusions

“…No drug-related AEs were reported beyond 2 years post-infusion. Longer-term safety data for this novel, and potentially curative, therapy option are needed, particularly given concerns regarding the possible risk of oncogene activation due to insertional mutagenesis [49]. Recently, the serious AE of acute myeloid leukemia (AML) reported in a related clinical trial of gene therapy in patients with sickle cell disease was determined to be very unlikely related to the lentiviral vector used; as such, the U.S. Food and Drug Administration (FDA) has lifted the hold on the ongoing clinical trials in patients with sickle cell and β-thalassemia [50].…”