Orphan Drugs and Potential Novel Approaches for Therapies of β-Thalassemia: Current Status and Future Expectations

ABSTRACT

Introduction: The β-thalassemias are rare diseases caused by more than 300 different mutations of the adult β-globin genes: they are treated with blood transfusions, chelation therapy or bone marrow transplantation.

Areas Covered: This article reviews orphan drugs, related patent applications and related clinical trials on β-thalassemia, including novel therapeutic approaches and repurposing of orphan drugs.

Expert Opinion: Patient stratification is expected to be applied for personalized therapeutic interventions for β-thalassemia patients. This will cover primary mutations of the β-globin gene and DNA polymorphisms that predict severity of the disease and response to therapy. Improved understanding of the regulation of γ-globin gene expression and the optimization of novel approaches for gene editing are expected to introduce innovative orphan drugs and/or approaches for fetal hemoglobin induction and gene correction, respectively. The possible combination between gene therapy and cellular therapy, including gene-correction, presents a new opportunity. A dramatic increase in the need for cellular biobanking (including also cord blood biobanking) is expected, given the possibility to intervene on patients-derived cells with bone marrow transplantation and/or generated induced pluripotent stem cells. The repurposing of drugs used in clinical trials for different pathologies is an interesting approach to providing novel drugs at low cost.

Keywords:

• β-Thalassemia
• orphan drugs
• fetal hemoglobin
• gene therapy
• gene editing
• drug repurposing

Article highlights

• β-Thalassemias are a group of hereditary human diseases caused by more than 300 mutations of the human β-globin gene.

• β-Thalassemia mutations cause in patients low or absent production of adult hemoglobin. Current treatment is based on blood transfusion and chelation therapy.

• Modification of the β-globin gene expression in β-thalassemia cells can be achieved by gene therapy or correction of the mutated β-globin gene.

• Cellular therapy has been applied to β-thalassemia, including reprogramming somatic cells of β-thalassemia patients to generate induced pluripotent stem cells, which can be genetically corrected.

• Therapeutically relevant production of fetal hemoglobin, beneficial for β-thalassemia, has been achieved with DNA-based approaches.

• Orphan drugs for β-thalassemia have been proposed on the major fields of development of therapeutic approaches.

• Repurposing of orphan drugs for β-thalassemia is expected to bring more bioactive molecules and therapeutic approaches for therapeutic trials.

This box summarizes key points contained in the article.

Acknowledgements

We would like to thank Dr Amanda Julie Neville MSB for her invaluable help in revising the scientific English of the manuscript.

Declaration of interest

R Gambari is supported by EU FP7 THALAMOSS Project (Thalassemia Modular Stratification System for Personalized Therapy of Β-Thalassemia; n. 306201-FP7-HEALTH-2012-INNOVATION-1), Fondazione Cariparo (Cassa di Risparmio di Padova e Rovigo), AVLT (Associazione Veneta per la Lotta alla Talassemia), CIB (Consorzio Interuniversitario per le Biotecnologie), Telethon (contract GGP10124), Wellcome Trust (contract 104744) and Rare-Partners Srl. MB is funded by Ministry of Health, Italy, Young Investigators-2009 (n. 098/GR-2009-1596647). 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.