Editors' ChoiceGene Therapy

Gene transfer delivers (β-globin)

See allHide authors and affiliations

Science Translational Medicine  02 May 2018:
Vol. 10, Issue 439, eaat8522
DOI: 10.1126/scitranslmed.aat8522


Transplantation of genetically engineered hematopoietic stem cells eliminates or reduces transfusion dependence in β-thalassemia.

Although the genetic basis of many diseases, including certain monogenic conditions, has been revealed, the ability to cure these diseases by correcting their underlying genetic defects has been limited. Indeed, the testing of gene therapy in humans has been marked by high-profile adverse events that include deaths from genotoxicity and from inflammatory response. Painful lessons have led to an increased appreciation for risks and to safer gene transfer technologies.

A recent report by Thompson et al. demonstrates progress in transplantation of genetically engineered autologous hematopoietic stem cells (HSCs) for the treatment of β-thalassemia, a monogenic hemoglobinopathy that is caused by variable mutations in the HBB gene. The primary clinical manifestation of severe dependent β-thalassemia is anemia with a lifelong requirement for red blood cell transfusion and iron chelation. Allogeneic HSC transplantation is a treatment option for some patients but is constrained by donor availability. To design a potentially curative treatment for all patients, the authors constructed a lentiviral vector for transfer of an extended HBB gene. This extended gene included segments of the locus control region for tissue-specific, insertion site-independent gene expression. Twenty-two patients were treated with myeloablative busulfan conditioning followed by transplantation of genetically engineered autologous HSCs. Fifteen patients became transfusion independent, and the others showed varying degrees of improvement in transfusion requirements. Importantly, no genotoxic adverse events occurred. Vector integration site analysis on peripheral blood revealed diverse polyclonal integration sites and no clonal dominance, and replication-competent lentivirus was not detected in any patient.

These findings demonstrate the clinical potential of a gene therapy in a morbid disease that affects thousands of patients. Although additional follow-up and the study of more patients are required, these results are a step forward in establishing the safety of lentiviral transduction of HSCs. This study, along with other recent progress in cellular and gene therapy, gives hope that the field may be at the threshold of delivering major benefit to patients.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article