Bezzerri Valentino, Lentini Laura, Api Martina, Busilacchi Elena Marinelli, Cavalieri Vincenzo, Pomilio Antonella, Diomede Francesca, Pegoraro Anna, Cesaro Simone, Poloni Antonella, Pace Andrea, Trubiani Oriana, Lippi Giuseppe, Pibiri Ivana, Cipolli Marco
Cystic Fibrosis Center of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy.
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, 90128 Palermo, Italy.
Biomedicines. 2022 Apr 12;10(4):886. doi: 10.3390/biomedicines10040886.
Shwachman-Diamond syndrome (SDS) is one of the most commonly inherited bone marrow failure syndromes (IBMFS). In SDS, bone marrow is hypocellular, with marked neutropenia. Moreover, SDS patients have a high risk of developing myelodysplastic syndrome (MDS), which in turn increases the risk of acute myeloid leukemia (AML) from an early age. Most SDS patients are heterozygous for the c.183-184TA>CT (K62X) SBDS nonsense mutation. Fortunately, a plethora of translational read-through inducing drugs (TRIDs) have been developed and tested for several rare inherited diseases due to nonsense mutations so far. The authors previously demonstrated that ataluren (PTC124) can restore full-length SBDS protein expression in bone marrow stem cells isolated from SDS patients carrying the nonsense mutation K62X. In this study, the authors evaluated the effect of a panel of ataluren analogues in restoring SBDS protein resynthesis and function both in hematological and non-hematological SDS cells. Besides confirming that ataluren can efficiently induce SBDS protein re-expression in SDS cells, the authors found that another analogue, namely NV848, can restore full-length SBDS protein synthesis as well, showing very low toxicity in zebrafish. Furthermore, NV848 can improve myeloid differentiation in bone marrow hematopoietic progenitors, enhancing neutrophil maturation and reducing the number of dysplastic granulocytes in vitro. Therefore, these findings broaden the possibilities of developing novel therapeutic options in terms of nonsense mutation suppression for SDS. Eventually, this study may act as a proof of concept for the development of similar approaches for other IBMFS caused by nonsense mutations.
施瓦赫曼-戴蒙德综合征（SDS）是最常见的遗传性骨髓衰竭综合征（IBMFS）之一。在SDS中，骨髓细胞减少，伴有明显的中性粒细胞减少。此外，SDS患者发生骨髓增生异常综合征（MDS）的风险很高，这反过来又会从小就增加急性髓系白血病（AML）的风险。大多数SDS患者是c.183-184TA>CT（K62X）SBDS无义突变的杂合子。幸运的是，到目前为止，已经开发并测试了大量用于治疗由无义突变引起的几种罕见遗传性疾病的翻译通读诱导药物（TRIDs）。作者之前证明，阿他芦胺（PTC124）可以在从携带无义突变K62X的SDS患者中分离出的骨髓干细胞中恢复全长SBDS蛋白的表达。在这项研究中，作者评估了一组阿他芦胺类似物在恢复血液学和非血液学SDS细胞中SBDS蛋白再合成及功能方面的作用。除了证实阿他芦胺可以在SDS细胞中有效诱导SBDS蛋白重新表达外，作者还发现另一种类似物NV848也可以恢复全长SBDS蛋白的合成，并且在斑马鱼中显示出非常低的毒性。此外，NV848可以改善骨髓造血祖细胞中的髓系分化，在体外增强中性粒细胞成熟并减少发育异常的粒细胞数量。因此，这些发现拓宽了在SDS的无义突变抑制方面开发新治疗选择的可能性。最终，这项研究可能为开发针对由无义突变引起的其他IBMFS的类似方法提供概念验证。
