The safety and effectiveness of genetically corrected iPSCs derived from \u03b2-thalassaemia patients in nonmyeloablative \u03b2-thalassaemic mice

Yexing Xian,Yi Yang,Zeyu Xiong,Shuming Ouyang,Xiaofang Sun,Haoxian Li,Yuhuan Xie,Zhanhui Ou,Yingjun Xie,Bing Song

doi:10.1186/s13287-020-01765-w

Abstract

Backgroundβ-Thalassaemia is a clinically common cause of hereditary haemolytic anaemia stemming from mutations in important functional regions of the β-globin gene. The rapid development of gene editing technology and induced pluripotent stem cell (iPSC)-derived haematopoietic stem cell (HSC) transplantation has provided new methods for curing this disease.MethodsGenetically corrected β-thalassaemia (homozygous 41/42 deletion) iPSCs that were previously established in our laboratory were induced to differentiate into HSCs, which were transplanted into a mouse model of IVS2–654 β-thalassaemia (B6;129P2-Hbbtm2Unc/J mice) after administration of an appropriate nonmyeloablative conditioning regimen. We also investigated the safety of this method by detecting the incidence of tumour formation in these mice after transplantation.ResultsThe combination of 25 mg/kg busulfan and 50 mg/(kg day) cyclophosphamide is an ideal nonmyeloablative protocol before transplantation. Genetically corrected β-thalassaemic HSCs survived and differentiated in nonmyeloablated thalassaemia mice. No tumour formation was observed in the mice for 10 weeks after transplantation.ConclusionOur study provides evidence that the transplantation of genetically corrected, patient-specific iPSCs could be used to cure genetic diseases, such as β-thalassaemia major.

Highlights

Introduction βThalassaemia is one of the most common autosomal recessive disorders worldwide [1]
Many researchers have attempted to determine the curative effect of Induced pluripotent stem cell (iPSC) transplantation on haematological disease by using total body irradiation (TBI) or radiation combined with myeloablative drugs as pretreatment before transplantation, but the observed effects were not those expected [15, 16]
Our results demonstrated that genetically corrected, iPSCderived haematopoietic stem cell (HSC) can differentiate in vivo and produce human β-globin in a mouse model, and the mice that received transplants lived for over 10 weeks without tumour formation

Summary

Introduction

Introduction βThalassaemia is one of the most common autosomal recessive disorders worldwide [1]. Regardless of the genotype, the classification and severity of this disease are based primarily on haemoglobin (HB) levels and clinical tolerability. This genetically inherited disease, which is prevalent throughout southern China, has threatened millions of people’s lives for decades, but no effective treatments are available. Gene therapy with haematopoietic stem/progenitor cells (HSPCs) has been clinically used for the treatment of β-thalassaemia, and its efficacy and safety are still under evaluation, it has shown promising therapeutic effects [7,8,9]. HSCs can be obtained from embryoid bodies formed in the presence of haematopoietic cytokines or from cocultures of iPSCs with stromal cells [14]. Many researchers have attempted to determine the curative effect of iPSC transplantation on haematological disease by using total body irradiation (TBI) or radiation combined with myeloablative drugs as pretreatment before transplantation, but the observed effects were not those expected [15, 16]

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