Bezzerri Valentino, Pegoraro Anna, Hristodor Anca Manuela, Crane Genevieve M, Meneghelli Ilaria, Brignole Cecilia, Boni Christian, Baldisseri Elena, Vella Antonio, Menichetti Giacomo, Valli Roberto, Porta Giovanni, D'Amico Giovanna, Tecchio Cristina, Parisi Alice, Lippi Giuseppe, Mercuri Angela, Cesaro Simone, Corey Seth J, Cipolli Marco
Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
Department of Life Sciences, Health and Health Professions, Link Campus University, Rome, Italy.
Nat Commun. 2025 Sep 2;16(1):8189. doi: 10.1038/s41467-025-63137-3.
Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, neutropenia, and a high risk of myeloid malignancy. Most patients with SDS harbor nonsense mutations in Shwachman-Bodian-Diamond syndrome gene (SBDS), which encodes a ribosome assembly factor. We investigated the translational read-through effect of ataluren in three patients with SDS undergoing a compassionate use program for twelve months. The primary and secondary endpoints were restoring SBDS protein levels in hematopoietic cells and improving myelopoiesis, respectively. SBDS synthesis increased in hematopoietic cells, whereas the bone marrow showed improved cellularity with the maturation of myeloid progenitors. In parallel, absolute neutrophil count was improved in two out of three patients, whereas platelet count increased in all recruited patients. Ataluren treatment normalized mTOR phosphorylation in peripheral blood monocytes and lymphocytes, suggesting a reduction of ribosomal stress. The exocrine pancreatic function also improved. Although the reduced sample size may represent a major limitation of this work, our findings strongly encourages the further clinical development of ataluren to treat SDS.
施瓦赫曼-戴蒙德综合征（SDS）的特征为外分泌胰腺功能不全、中性粒细胞减少以及髓系恶性肿瘤的高风险。大多数SDS患者在施瓦赫曼-博迪安-戴蒙德综合征基因（SBDS）中存在无义突变，该基因编码一种核糖体组装因子。我们对三名参与同情用药计划达十二个月的SDS患者研究了阿他芦胺的翻译通读效应。主要终点和次要终点分别是恢复造血细胞中的SBDS蛋白水平以及改善骨髓生成。造血细胞中SBDS合成增加，而骨髓显示随着髓系祖细胞成熟细胞增多。同时，三名患者中有两名的绝对中性粒细胞计数得到改善，而所有招募患者的血小板计数均增加。阿他芦胺治疗使外周血单核细胞和淋巴细胞中的mTOR磷酸化正常化，提示核糖体应激减轻。外分泌胰腺功能也得到改善。尽管样本量减少可能是这项研究的一个主要局限，但我们的发现有力地鼓励了阿他芦胺治疗SDS的进一步临床开发。
