Gene Therapy for Severe Haemoglobin Disorders

Abstract

Sickle cell disease (SCD) and β‐thalassaemia result from inherited mutations that cause structural abnormality or deficient synthesis of adult haemoglobin. Palliative therapies improve the quality/duration of life for many, but side effects result from long‐term use. Bone marrow transplantation can be curative, but is limited to individuals with a matched donor. Thus, gene delivery into the patient's haematopoietic stem cells is a desirable therapy. Lentiviral vectors encoding for erythroid‐specific expression of either γ‐ or β‐globin genes have been developed for this purpose. These vectors have been used to cure SCD and β‐thalassaemia in mouse models with positive results emerging from clinical trials. Concurrently, innovative strategies intending to reactivate endogenous γ‐globin expression or correct β‐globin mutations at the genome level are showing promise for the future. Ultimately, clinical utility of all these approaches depend on safety and efficacy so that a cure can be consistently achieved. Key Concepts: Sickle cell disease (SCD) and β‐thalassaemia are the most common single gene disorders, and a worldwide health concern. The switch from foetal to adult haemoglobin production after birth marks the onset of disease. Haematopoietic stem cell transplant is curative, but available to only a limited number of patients making gene therapy a highly desirable alternative. Lentiviral vectors made possible the delivery of complex, erythroid‐specific globin expression cassettes into haematopoietic stem cells. Mouse models of SCD and β‐thalassaemia have been cured with lentiviral vectors encoding for high‐level, erythroid specific expression of γ‐ and β‐globin genes. The first adult β‐thalassaemia major patient treated with a β‐globin lentiviral vector remains transfusion‐independent and in good health 6 years after therapy.

The potential of gene therapy approaches for the treatment of hemoglobinopathies: achievements and challenges

“…There are presently no clinical trials for α-thalassemia. The lentiviral vectors used in the above trials have been extensively reviewed previously and summarized briefly below; readers are directed to the following reviews for a more indepth discussion [Villamizar et al 2001; Dong et al 2013; Finotti et al 2015].…”