Reticular dysgenesis (RD) is a rare genetic disease caused by gene mutations in the ATP:AMP phosphotransferase, adenylate kinase 2 (AK2). Patients with RD suffer from severe combined immunodeficiency with neutrophil maturation arrest. Although hematopoietic stem cell transplantation can be a curative option, it is invasive, and complications of agranulocytosis-induced infection worsen the prognosis. Here, we report that the use of UK-5099, an inhibitor of the mitochondrial pyruvate carrier (MPC), on hemo-angiogenic progenitor cells (HAPCs) derived from AK2-deficient induced pluripotent stem cells improved neutrophil maturation. Reactive oxygen species (ROS) levels in AK2-deficient HAPCs remained unchanged throughout all experiments, implying that UK-5099 improved the phenotype without affecting ROS levels. Overall, our results suggest that the MPC is a potential therapeutic target for the treatment of neutrophil maturation defects in RD.

网状发育不全 (RD) 是一种罕见的遗传性疾病，由 ATP:AMP 磷酸转移酶、腺苷酸激酶 2 (AK2) 基因突变引起。 RD 患者患有严重的联合免疫缺陷和中性粒细胞成熟停滞。尽管造血干细胞移植可能是一种治疗选择，但它是侵入性的，并且粒细胞缺乏症引起的感染的并发症会使预后恶化。在这里，我们报告使用 UK-5099（一种线粒体丙酮酸载体 (MPC) 抑制剂）对源自 AK2 缺陷诱导多能干细胞的血血管生成祖细胞 (HAPC) 改善中性粒细胞成熟。在所有实验中，AK2 缺陷的 HAPC 中的活性氧 (ROS) 水平保持不变，这意味着 UK-5099 在不影响 ROS 水平的情况下改善了表型。总的来说，我们的结果表明 MPC 是治疗 RD 中性粒细胞成熟缺陷的潜在治疗靶点。