A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in non-transfusion-dependent as well as transfusion-dependent β-thalassemia (BT) patients. Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion-dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that TMPRSS6-ASO could improve iron parameters and iron overload when co-administered with luspatercept. We used an agent analogous to murine luspatercept (RAP-GRL) and another novel therapeutic, IONIS TMPRSS6-LRx (TMPRSS6-ASO), a hepcidin inducer, to treat non-transfusion-dependent BT-intermedia mice. Our study shows that RAP-GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast, TMPRSS6-ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre-clinical support for combining TMPRSS6-ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.

中文翻译：

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TGF-β 配体捕获器 (RAP-GRL) 和 TMPRSS6-ASO 的组合对于纠正 β-地中海贫血效果更佳


最近批准的一种诱导红细胞成熟的药物（luspatercept）已被证明可以改善贫血并减少非输血依赖性和输血依赖性β地中海贫血（BT）患者的输血需求。尽管这些结果主要是积极的，但并非所有患者都表现出预期的血红蛋白 (Hb) 水平增加或输血负担减轻。其他研究表明，在输血依赖性 BT 中给予 luspatercept 与红细胞生成标记物增加、铁调素水平降低和肝铁含量增加相关。总而言之，这些研究表明 luspatercept 可能需要额外的药物来改善红细胞和铁的管理。由于 luspatercept 似乎不会直接影响铁代谢，我们假设 TMPRSS6-ASO 与 luspatercept 共同给药时可以改善铁参数和铁超负荷。我们使用类似于鼠 luspatercept (RAP-GRL) 的药物和另一种新型治疗剂 IONIS TMPRSS6-LRx (TMPRSS6-ASO)（一种铁调素诱导剂）来治疗非输血依赖性 BT-intermedia 小鼠。我们的研究表明，单独使用 RAP-GRL 可以改善红细胞 (RBC) 的产生，但对脾肿大和铁参数没有影响或影响有限。相比之下，TMPRSS6-ASO 最有效地改善了红细胞测量、改善了脾肿大并改善了铁过载。我们的结果为 TMPRSS6-ASO 和 luspatercept 联合治疗 BT 提供了临床前支持，因为这些药物一起显示出同时改善 BT 患者红细胞和铁参数的潜力。