Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Abstract

<jats:p>Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.</jats:p>

Somatic mosaicism in patients with Fanconi anaemia: Proposal of alternative tissue for inconclusive diagnoses

“…Fanconi anaemia (FA) is a rare disease with heterogeneous genetic and phenotypic features characterized by progressive bone marrow failure (BMF), chromosomal fragility, congenital abnormalities, and increased predisposition to haematological malignancies and solid tumours 1,2 . Haematopoietic stem cell transplantation (HSCT) is a curative treatment that can lead to hematologic healing 3,4 .…”

Deciphering the molecular mechanism of stop codon readthrough

“…It also outlines the potential of this mechanism in terms of basic science and clinical applications to advance understanding of pathways of gene expression and in the development of therapeutic approaches for nonsense‐mutation‐related genetic diseases. Potential clinical applications of a stop codon readthrough strategy have recently been discussed in several reviews (Dabrowski, Bukowy‐Bieryllo, & Zietkiewicz, 2018; Bezzerri et al ., 2020; Morais, Adachi, & Yu, 2020; Sharma, Keeling, & Rowe, 2020), hence we focus here on the molecular mechanisms leading to stop codon readthrough.…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…Nonsense mutations are found in about 11% of genetic disorders such as cystic fibrosis (CF) [ 17 ], Duchenne muscular dystrophy (DMD) [ 18 ], spinal muscular atrophy [ 19 , 20 ], neurofibromatosis [ 21 ], retinitis pigmentosa [ 22 , 23 , 24 ], lysosomal storage disease [ 13 , 25 , 26 ], Rett syndrome [ 27 ], Shwachman–Diamond syndrome [ 28 , 29 ], and Usher’s syndrome (USH) [ 30 ]. In this context and despite its limits, the translational readthrough of PTCs can represent a valuable pharmaceutical approach to target the specific genetic defect caused by nonsense mutations.…”