Manipulation of Developmental Gamma-Globin Gene Expression: an Approach for Healing Hemoglobinopathies

ABSTRACT

β-Hemoglobinopathies are the most common monogenic disorders, and a century of research has provided us with a better understanding of the attributes of these diseases. Allogenic stem cell transplantation was the only potentially curative option available for these diseases until the discovery of gene therapy. The findings on the protective nature of fetal hemoglobin in sickle cell disease (SCD) and thalassemia patients carrying hereditary persistence of fetal hemoglobin (HPFH) mutations has given us the best evidence that the cure for β-hemoglobinopathies remains hidden in the hemoglobin locus. The detailed understanding of the developmental gene regulation of gamma-globin (γ-globin) and the emergence of gene manipulation strategies offer us the opportunity for developing a γ-globin gene-modified autologous stem cell transplantation therapy. In this review, we summarize different therapeutic strategies that reactivate fetal hemoglobin for the gene therapy of β-hemoglobinopathies.

KEYWORDS:

• hemoglobinopathies
• gene editing
• hematopoietic stem cells

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Article of Significant Interest in This Issue

ACKNOWLEDGMENTS

Funding was provided by the Department of Biotechnology, Government of India (BT/PR17316/MED/31/326/2015 and BT/PR31616/MED/31/408/2019). P.B. is supported by a Junior Research Fellowship from the Council of Scientific and Industrial Research (CSIR).