PDF(Pubmed)
Abstract：
Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.
摘要：
Shwachman-Diamond综合征（SDS）的特征是中性粒细胞减少症，胰腺外分泌功能不全和骨骼异常。SDS骨髓造血祖细胞显示凋亡增加和粒细胞分化受损。Shwachman-Bodian-Diamond综合征（SBDS）表达的丧失导致真核80S核糖体成熟减少。在~90%的SDS患者中发现SBDS基因的双等位基因突变,其中约55％携带c.183-184TA>CT无义突变。已经开发了几种旨在抑制无义突变的翻译连读诱导药物。其中一个,Ataluren,已在欧洲获得Duchenne型肌营养不良症治疗的批准。我们先前表明，ataluren可以恢复SDS衍生的骨髓细胞中全长SBDS蛋白的合成。这里,我们扩展了我们的临床前研究，以评估体外和离体SBDS功能的恢复。Ataluren改善了SDS衍生细胞中80S核糖体组装和总蛋白合成，骨髓祖细胞中恢复的骨髓生成，改善体外中性粒细胞趋化性和减少体外中性粒细胞增生异常标志物。Ataluren还恢复了原代成骨细胞的全长SBDS合成，这表明它的有益作用可能超出了骨髓间隔。总之,我们的结果加强了在携带无义突变的SDS患者中进行atalurenI/II期临床试验的理由.
