Gene-Targeted Therapies in Inherited Bone Marrow Failure Syndromes

Abstract

Inherited bone marrow failure syndromes (IBMFS) are genetically heterogeneous multiorgan disorders sharing defective hematopoiesis and cancer predisposition. Here, we examine emerging strategies to suppress nonsense mutations, with a focus on translational readthrough-inducing drugs (TRIDs), nonsense-mediated decay modulation and anticodon-edited tRNAs. In addition, we discuss gene therapy and genome-editing approaches developed for IBMFS caused by other types of pathogenic variants. Ataluren, the most clinically advanced non-aminoglycoside TRID, has shown preclinical and early clinical activity in Shwachman-Diamond syndrome, including an increased synthesis of neomorphic SBDS protein, improved ribosome biogenesis, reduced stress signaling, enhanced myeloid maturation and partial hematological benefit. In Fanconi anemia models, ataluren induced neomorphic FANC protein expression, reduced DNA damage responses and improved resistance to genotoxic stress, while also showing mutation-independent effects on mitochondrial and metabolic dysfunction. Nonsense-mediated decay (NMD) inhibition and anticodon-edited (ACE)-tRNAs may further enhance nonsense suppression by increasing mutant transcript availability or enabling the proper amino acid insertion at PTCs, respectively. In parallel, gene therapy and genome editing are advancing, with clinical proof of concept in Fanconi anemia, GATA1 rescue in Diamond-Blackfan anemia and ELANE-targeted editing in severe congenital neutropenia. Overall, these approaches should be developed through genotype-informed, pathway-based and biomarker-driven precision medicine workflows integrating ex vivo responder testing with molecular and clinical endpoints.