Novel Translational Read-through-Inducing Drugs as a Therapeutic Option for Shwachman-Diamond Syndrome.
Valentino BezzerriLaura LentiniMartina ApiElena Marinelli BusilacchiVincenzo CavalieriAntonella PomilioFrancesca DiomedeAnna PegoraroSimone CesaroAntonella PoloniAndrea PaceOriana TrubianiGiuseppe LippiIvana PibiriMarco CipolliPublished in: Biomedicines (2022)
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.
Keyphrases
- bone marrow
- end stage renal disease
- acute myeloid leukemia
- stem cells
- mesenchymal stem cells
- chronic kidney disease
- ejection fraction
- newly diagnosed
- prognostic factors
- binding protein
- immune response
- magnetic resonance imaging
- cell death
- dendritic cells
- acute lymphoblastic leukemia
- small molecule
- long non coding rna