Emerging therapies in β-thalassemia: toward a new era in management

ABSTRACT

Introduction

The thalassemias are among the most  common inherited monogenic diseases worldwide, characterized by autosomal recessive inherited defects in the production of hemoglobin. Currently available conventional therapies have many challenges and limitations. Advances in understanding the underlying pathophysiology of β-thalassemia enabled clinicians and researchers to move toward the development of novel therapeutic modalities. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload.

Areas covered

In this review, we will provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.

Expert opinion

A thorough understanding of the pathophysiology and overall disease burden of β-thalassemia has aided clinicians and scientists to optimize disease management approaches and construct a plan for the development of novel therapies, with ultimate goals of prolonging longevity, reducing symptom burden, improving compliance and adherence for a better quality of life.

KEYWORDS:

• Thalassemia
• ineffective erythropoiesis
• iron overload
• hepcidin
• JAK2
• novel therapies
• gene therapy
• luspatercept
• genome editing
• sotatercept

Article highlights

• Several novel therapeutic targets in β-thalassemia have been identified that can ameliorate the genetic defect, ineffective erythropoiesis, anemia and transfusion-dependence.

• Targeting ineffective erythropoiesis through activin II receptor traps has the potential to decrease transfusion requirement in TDT and increase Hb levels in NTDT patients.

• Preliminary data of the use of JAK2 inhibitors in β-thalassemia are encouraging but further research is needed to establish effects and utility.

• Therapeutic strategies aiming at improving iron dysregulation such as minihepcidin and TMPRSS6 inhibitors are also showing promise.

• The use of gene therapy through globin lentiviral vectors present the most advanced approach for treating hemoglobinopathies such as β-thalassemia.

• Genome editing approaches to inhibit the BCL11A gene have also been described and are currently in pre-clinical stage.

Declaration of interest

A Taher reports receiving consultancy, research funding, and honoraria from Novartis; research funding and consultancy from Celgene; consultancy from Vifor, research funding and consultancy from Protagonist Therapeutics; research funding and consultancy from La Jolla Pharmaceuticals; Consultancy from IONIS Pharmaceuticals. The authors have no other 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 apart from those disclosed.”

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.