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HBB-deficient Macaca fascicularis monkey presents with human β-thalassemia

2019; Springer Science+Business Media; Volume: 10; Issue: 7 Linguagem: Inglês

10.1007/s13238-019-0627-y

1674-8018

Yan Huang, Chenhui Ding, Puping Liang, Duanduan Li, Yu Tang, Meng Wei, Hongwei Sun, Hongyu Lu, Yu Chen, Xueying Chen, Qunshan Huang, Jian‐Pei Fang, Canquan Zhou, Shihua Yang, Junjiu Huang,

Drug Transport and Resistance Mechanisms

HBB-deficient Macaca fascicularis monkey presents with human β-thalassemiaDear Editor, β-Thalassemia is a common severe genetic disease caused by mutations in HBB and affects approximately 1.5% of the global population (Origa, 2017).In southern China, the carrier rate of β-thalassemia is as high as 6.43%, creating a high socio-economic burden (Xiong et al., 2010).In adult humans, there are three types of hemoglobin: HbA1 (∼97%), HbA2 (∼2%) and HbF (∼1%).HbA1 (α 2 β 2 ) is composed of two α-globin and two β-globin subunits encoded by HBA and HBB, respectively; HbF (α 2 γ 2 ) is made up of two α-globin subunits and two γ-globin subunits encoded by HBG.Mutations in the coding region or regulatory region of HBB are involved in β-thalassemia pathogenesis.Except for some rare dominant mutations, most HBB mutations are recessive (Origa, 2017).Depending on the mutation type, the β-globin level will either be reduced or completely depleted, resulting in α-globin accumulation and precipitation.These α-globin precipitates lead to red blood cell death, resulting in anemia and tissue damage, and even death in βthalassemia major patients.Blood transfusions can help slow disease progression but lead to iron overload, ultimately resulting in iron toxicity.Bone marrow transfer is the only cure in the clinic and is available only to a small percentage of patients with human leukocyte antigen-matched donors.Recently, gene therapy and gene editing therapy have shown great promise in curing β-thalassemia (Glaser et al., 2015;Thompson et al., 2018).However, no appropriate animal models are available for evaluating the safety and efficacy of such advanced therapeutic strategies in vivo.β-thalassemia mice are the sole animal model available for research.However, substantial differences have been reported between the types and expression patterns of human and mouse globins (McColl and Vadolas, 2016).Moreover, mice contain no fetal globin gene equivalent, and homozygous mutations of HBB in mouse for early models of β-thalassemia major or Cooley anemia are all embryonic lethal (Huo et al., 2009).Recently, significant phenotype and physiology differences have been reported between SIRT6null mice and the non-human primate model (Zhang et al., 2018).Thus, an appropriate non-human primate model is needed for human β-thalassemia studies and treatments.