Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

Abstract

Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.

Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms

“…Are the in vitro results presented here indicative of ataluren's effect in cells and relevant for ongoing efforts to develop new, more potent TRIDs as therapies for PSC diseases (10,13,(46)(47)(48)(49)? Supporting cell biological and health care relevance is the straightforward manner in which restricting ataluren's effect to inhibition of termination explains its lack of stimulation of misreading at normal codons in cellular assays (50).…”

Molecular Insights into Determinants of Translational Readthrough and Implications for Nonsense Suppression Approaches

“…A different approach based on high-throughput screening of small molecular weight compounds libraries led to the identification of non-aminoglycoside molecules with readthrough-induction activity [ 85 , 86 , 87 ]. One paradigmatic example is PTC124 (also known as ataluren or Translarna ® ), an orally bioavailable oxadiazole compound with PTC suppression activity that has been shown to be safe, with minimal off-target side-effects and no antibacterial activity [ 85 ].…”

“…Since the first attempt by Howard and colleagues in 1996 [ 64 ], several relevant diseases have been challenged with this correction strategy, including Duchenne/Becker dystrophy [ 68 , 114 , 115 , 116 , 117 , 118 ], cystic fibrosis [ 119 , 120 , 121 , 122 , 123 , 124 ], and spinal muscular atrophy [ 84 , 125 , 126 ]. Broad information on the efficacy of drug-induced readthrough for these disease models, as well as a detailed discussion on readthrough -inducing compounds, have been recently reviewed [ 87 , 127 , 128 , 129 ]. In addition, further details on approaches related to stop codon suppression or other strategies for the correction of molecular defects in genetic disorders have also been described [ 130 , 131 , 132 ].…”

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

“…Furthermore, ataluren has shown less toxicity and better safety tolerability than aminoglycosides [212,214]. This last feature arises from the fact that ataluren displays its therapeutic activity at concentration much lower (i.e., 3 µM) than gentamicin (i.e., 1 mM) and other aminoglycosides [5,178,197]. It has been demonstrated that the readthrough efficacy of ataluren depends on the sequence of the premature termination codon (PTC) (UAA<UAG<UGA) as well as the sequences of the flanking regions of PTC [195,196,215].…”

“…Alternatively, nonsense suppression therapy may be designed to reduce the nonsense mediated decay (NMD) induced by the nonsense mutations. NMD is an evolutionarily conserved defense mechanism of eukaryotic cells that surveys newly synthesized mRNA and degrades transcripts containing a PTC [4,5].…”