Mitapivat, a pyruvate kinase activator, shows great potential as a sickle cell disease (SCD)-modifying therapy. The safety and efficacy of mitapivat as a long-term maintenance therapy are currently being evaluated in two open-label studies. Here we applied a comprehensive multi-omics approach to investigate the impact of activating pyruvate kinase on red blood cells (RBC) from 15 SCD patients. HbSS patients were enrolled in one of the open-label, extended studies (NCT04610866). Leukodepleted RBC obtained from fresh whole blood at baseline, prior to drug initiation, and at longitudinal timepoints over the course of the study were processed for multi-omics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBC. Mitapivat decreased 2,3-diphosphoglycerate levels, increased adenosine triphosphate levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of treatment, with minimal changes in reticulocyte counts. In the first 6 months of treatment there were also transient elevations of lysophosphatidylcholines and oxylipins with depletion of free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBC identified benefits for glycolysis, as well as activation of the Lands cycle.

中文翻译：

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镰状细胞病患者红细胞中丙酮酸激酶激活后 mitapivat 功效的功能和多组学特征。


Mitapivat 是一种丙酮酸激酶激活剂，显示出作为镰状细胞病 (SCD) 缓解疗法的巨大潜力。目前两项开放标签研究正在评估米塔皮伐作为长期维持治疗的安全性和有效性。在这里，我们应用综合多组学方法来研究激活丙酮酸激酶对 15 名 SCD 患者红细胞 (RBC) 的影响。 HbSS 患者参加了一项开放标签扩展研究 (NCT04610866)。在基线、药物开始前以及研究过程中的纵向时间点从新鲜全血中获得的去白细胞红细胞通过逐步提取代谢物、脂质和蛋白质进行多组学处理。 Mitapivat 治疗对 SCD RBC 的代谢组、脂质组和蛋白质组有显着影响。 Mitapivat 降低了 SCD 患者的 2,3-二磷酸甘油水平，增加了三磷酸腺苷水平，并改善了血液学和镰刀参数。组学测量和临床测量之间的一致性证实了 mitapivat 针对晚期糖酵解的特异性，其中糖酵解代谢物排名最高，与治疗期间血红蛋白 S 氧亲和力 (p50) 和镰状动力学 (t50) 参数相关。 Mitapivat 在开始治疗后 2 周内显着降低了线粒体来源的蛋白质水平，网织红细胞计数变化最小。在治疗的前 6 个月，溶血磷脂酰胆碱和氧脂素也出现短暂升高，同时游离脂肪酸减少，表明对膜脂重塑有影响。红细胞的多组学分析确定了糖酵解的益处以及 Lands 循环的激活。