Globin gene regulation for treating β-thalassemias: progress, obstacles and future

Abstract

Introduction: β-thalassemias result from mutations in the β-globin gene, leading to a reduced or absent production of β-globin chains. The treatment of β-thalassemias has been historically based on blood transfusions and iron chelation therapy. The only curative therapy currently available is allogeneic hematopoietic stem cell transplant (HSCT) from suitable donors. With the limited pool of suitable donors, HSCT remains unavailable for many thalassemic patients. They may instead benefit from globin gene therapy and other modalities, which exploit recent advances in understanding of globin gene regulation.

Areas covered: The objective of this review is to discuss the relevance of novel treatment modalities based on globin gene regulation, including globin gene transduction therapy, which is currently being studied in clinical trials. We also discuss globin gene editing, microRNA therapy, hypomethylating agents, hydroxyurea and butyrate derivatives.

Expert opinion: In the future and as a result of ongoing clinical trials, gene therapy, using lentiviral-based or other vectors, could be an alternative to allogeneic HSCT in patients with β-thalassemia. Gene editing is also a promising avenue that has not been explored in clinical trials yet.

Keywords:

• gene therapy
• genome editing
• globin
• hematopoietic stem cells
• thalassemia

Acknowledgments

AN Saliba and RS Alameddine contributed equally to this work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

This box summarizes key points contained in the article.