Novel Translational Read-through–Inducing Drugs as a Therapeutic Option for Shwachman-Diamond Syndrome

Biomedicines

Martina Api¹  Anna Pegoraro²  Valentino Bezzerri²  Marco Cipolli²  Antonella Pomilio³  Laura Lentini⁴  Ivana Pibiri⁴  Vincenzo Cavalieri⁴  Andrea Pace⁴  Francesca Diomede⁵  Oriana Trubiani⁵  Antonella Poloni⁶  Elena Marinelli Busilacchi⁶  Giuseppe Lippi⁷  Simone Cesaro⁸ 

[1] Cystic Fibrosis Center of Ancona, Azienda Ospedaliero Universitaria Ospedali Riuniti, 60126 Ancona, Italy;Cystic Fibrosis Center of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;Department of Medical, Oral and Biotechnological Sciences, G. D’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy;Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), University of Palermo, 90128 Palermo, Italy;Dipartimento di Tecnologie Innovative in Medicina e Odontoiatria, G. D’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy;Hematology Clinic, Università Politecnica delle Marche, AOU Ospedali Riuniti, 60126 Ancona, Italy;Section of Clinical Biochemistry, University of Verona, 37126 Verona, Italy;Unit of Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;

关键词: bone marrow failure syndromes;    ataluren;    neutropenia;   

DOI  :  10.3390/biomedicines10040886

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown