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Molecular Approaches Fighting Nonsense

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 December 2020) | Viewed by 43258

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Dr. Ivana Pibiri

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Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze Ed. 17, Parco d'Orleans, 90128 Palermo, Italy
Interests: synthesis of heterocyclic compounds; heterocyclic chemistry; medicinal and pharmaceutical chemistry; synthetic medicinal chemistry; natural product chemistry; materials chemistry; applied organic chemistry
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Dear Colleagues,

Nonsense mutations in the DNA generate a premature stop codon PTC in the coding region of the mRNA; protein translation is interrupted, thus producing truncated polypeptides that cannot express their function and are promptly detected by the nonsense mediated mRNA decay (NMD) pathway.

Nonsense mutations are responsible for different genetic disorders, e.g., cystic fibrosis, Duchenne muscular dystrophy, retinitis pigmentosa, congenital blindness, dystonia, spinal muscular atrophy, neurofibromatosis, lysosomal storage disease, usher’s syndrome, hemophilia, Tay–Sachs disease, Schwackman Diamond syndrome, and several forms of cancer, to cite a few.

While some therapies aim at diminishing the impact of symptoms of these diseases, recent research is facing the challenge of targeting the genetic defect itself, in the frame of a personalized medicine approach. An effective nonsense therapy is still far from being discovered, and many efforts are devoted to achieve the synthesis of a full-length protein from nonsense-mutated genes.

Correction of the genetic defect at the DNA level has been attempted through genome editing strategies in order to repair nonsense mutations at the transcriptional phase. On the other hand, drugs have been developed to target the translation phase and promote the bypass of PTC, allowing the synthesis of full-length functional protein, a strategy known as PTC “readthrough” by translational readthrough promoters (TRIDs).

New readthrough promoters, hypotheses on readthrough mechanism of action, also proposed on the basis of computational studies and complementary strategies to enhance the effect of TRIDs, are to be considered as a “hot topic” for the researchers working in the “nonsense” field.

Dr. Ivana Pibiri
Guest Editor

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Editorial

Jump to: Research, Review

2 pages, 169 KiB

Open AccessEditorial

Molecular Approaches Fighting Nonsense

by Ivana Pibiri

Int. J. Mol. Sci. 2021, 22(21), 11933; https://doi.org/10.3390/ijms222111933 - 3 Nov 2021

Cited by 1 | Viewed by 1509

Abstract

Nonsense mutations are the result of single nucleotide substitutions in the DNA that change a sense codon (coding for an amino acid) to a nonsense or premature termination codon (PTC) within the coding region of the mRNA [...] Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

Research

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14 pages, 1828 KiB

Open AccessArticle

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia

by Maciej Dabrowski, Zuzanna Bukowy-Bieryllo, Claire L. Jackson and Ewa Zietkiewicz

Int. J. Mol. Sci. 2021, 22(9), 4923; https://doi.org/10.3390/ijms22094923 - 7 May 2021

Cited by 11 | Viewed by 2899

Abstract

Primary ciliary dyskinesia (PCD) is a rare disease with autosomal recessive inheritance, caused mostly by bi-allelic gene mutations that impair motile cilia structure and function. Currently, there are no causal treatments for PCD. In many disease models, translational readthrough of premature termination codons (PTC-readthrough) induced by aminoglycosides has been proposed as an effective way of restoring functional protein expression and reducing disease symptoms. However, variable outcomes of pre-clinical trials and toxicity associated with long-term use of aminoglycosides prompt the search for other compounds that might overcome these problems. Because a high proportion of PCD-causing variants are nonsense mutations, readthrough therapies are an attractive option. We tested a group of chemical compounds with known PTC-readthrough potential (ataluren, azithromycin, tylosin, amlexanox, and the experimental compound TC007), collectively referred to as non-aminoglycosides (NAGs). We investigated their PTC-readthrough efficiency in six PTC mutations found in Polish PCD patients, in the context of cell and cilia health, and in comparison to the previously tested aminoglycosides. The NAGs did not compromise the viability of the primary nasal respiratory epithelial cells, and the ciliary beat frequency was retained, similar to what was observed for gentamicin. In HEK293 cells transfected with six PTC-containing inserts, the tested compounds stimulated PTC-readthrough but with lower efficiency than aminoglycosides. The study allowed us to select compounds with minimal negative impact on cell viability and function but still the potential to induce PTC-readthrough. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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20 pages, 4207 KiB

Open AccessArticle

Synergy between Readthrough and Nonsense Mediated Decay Inhibition in a Murine Model of Cystic Fibrosis Nonsense Mutations

by Daniel R. McHugh, Calvin U. Cotton and Craig A. Hodges

Int. J. Mol. Sci. 2021, 22(1), 344; https://doi.org/10.3390/ijms22010344 - 31 Dec 2020

Cited by 20 | Viewed by 3517

Abstract

Many heritable genetic disorders arise from nonsense mutations, which generate premature termination codons (PTCs) in transcribed mRNA. PTCs ablate protein synthesis by prematurely terminating the translation of mutant mRNA, as well as reducing mutant mRNA quantity through targeted degradation by nonsense-mediated decay (NMD) mechanisms. Therapeutic strategies for nonsense mutations include facilitating ribosomal readthrough of the PTC and/or inhibiting NMD to restore protein function. However, the efficacy of combining readthrough agents and NMD inhibitors has not been thoroughly explored. In this study, we examined combinations of known NMD inhibitors and readthrough agents using functional analysis of the CFTR protein in primary cells from a mouse model carrying a G542X nonsense mutation in Cftr. We observed synergy between an inhibitor of the NMD component SMG-1 (SMG1i) and the readthrough agents G418, gentamicin, and paromomycin, but did not observe synergy with readthrough caused by amikacin, tobramycin, PTC124, escin, or amlexanox. These results indicate that treatment with NMD inhibitors can increase the quantity of functional protein following readthrough, and that combining NMD inhibitors and readthrough agents represents a potential therapeutic option for treating nonsense mutations. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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18 pages, 3344 KiB

Open AccessArticle

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

by Ivana Pibiri, Raffaella Melfi, Marco Tutone, Aldo Di Leonardo, Andrea Pace and Laura Lentini

Int. J. Mol. Sci. 2020, 21(17), 6420; https://doi.org/10.3390/ijms21176420 - 3 Sep 2020

Cited by 13 | Viewed by 4696

Abstract

Cystic fibrosis (CF) patients develop a severe form of the disease when the cystic fibrosis transmembrane conductance regulator (CFTR) gene is affected by nonsense mutations. Nonsense mutations are responsible for the presence of a premature termination codon (PTC) in the mRNA, creating a lack of functional protein. In this context, translational readthrough-inducing drugs (TRIDs) represent a promising approach to correct the basic defect caused by PTCs. By using computational optimization and biological screening, we identified three new small molecules showing high readthrough activity. The activity of these compounds has been verified by evaluating CFTR expression and functionality after treatment with the selected molecules in cells expressing nonsense–CFTR–mRNA. Additionally, the channel functionality was measured by the halide sensitive yellow fluorescent protein (YFP) quenching assay. All three of the new TRIDs displayed high readthrough activity and low toxicity and can be considered for further evaluation as a therapeutic approach toward the second major cause of CF. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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16 pages, 4649 KiB

Open AccessArticle

Investigating REPAIRv2 as a Tool to Edit CFTR mRNA with Premature Stop Codons

by Raffaella Melfi, Patrizia Cancemi, Roberta Chiavetta, Viviana Barra, Laura Lentini and Aldo Di Leonardo

Int. J. Mol. Sci. 2020, 21(13), 4781; https://doi.org/10.3390/ijms21134781 - 6 Jul 2020

Cited by 10 | Viewed by 3563

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the transmembrane conductance regulator (CFTR) protein. Some CF patients are compound heterozygous or homozygous for nonsense mutations in the CFTR gene. This implies the presence in the transcript of premature termination codons (PTCs) responsible for a truncated CFTR protein and a more severe form of the disease. Aminoglycoside and PTC124 derivatives have been used for the read-through of PTCs to restore the full-length CFTR protein. However, in a precision medicine framework, the CRISPR/dCas13b-based molecular tool “REPAIRv2” (RNA Editing for Programmable A to I Replacement, version 2) could be a good alternative to restore the full-length CFTR protein. This RNA editing approach is based on the targeting of the deaminase domain of the hADAR2 enzyme fused to the dCas13b protein to a specific adenosine to be edited to inosine in the mutant mRNA. Targeting specificity is allowed by a guide RNA (gRNA) complementarily to the target region and recognized by the dCas13b protein. Here, we used the REPAIRv2 platform to edit the UGA PTC to UGG in different cell types, namely IB3-1 cells, HeLa, and FRT cells engineered to express H2BGFP^opal and CFTR^W1282X, respectively. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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18 pages, 2587 KiB

Open AccessArticle

Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

by Ananya Samanta, Katarina Stingl, Susanne Kohl, Jessica Ries, Joshua Linnert and Kerstin Nagel-Wolfrum

Int. J. Mol. Sci. 2019, 20(24), 6274; https://doi.org/10.3390/ijms20246274 - 12 Dec 2019

Cited by 29 | Viewed by 4773

Abstract

The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2A^G3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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Review

Jump to: Editorial, Research

25 pages, 2706 KiB

Open AccessReview

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

by Silvia Lombardi, Maria Francesca Testa, Mirko Pinotti and Alessio Branchini

Int. J. Mol. Sci. 2020, 21(24), 9449; https://doi.org/10.3390/ijms21249449 - 11 Dec 2020

Cited by 18 | Viewed by 4355

Abstract

The fidelity of protein synthesis, a process shaped by several mechanisms involving specialized ribosome regions and external factors, ensures the precise reading of sense and stop codons. However, premature termination codons (PTCs) arising from mutations may, at low frequency, be misrecognized and result in PTC suppression, named ribosome readthrough, with production of full-length proteins through the insertion of a subset of amino acids. Since some drugs have been identified as readthrough inducers, this fidelity drawback has been explored as a therapeutic approach in several models of human diseases caused by nonsense mutations. Here, we focus on the mechanisms driving translation in normal and aberrant conditions, the potential fates of mRNA in the presence of a PTC, as well as on the results obtained in the research of efficient readthrough-inducing compounds. In particular, we describe the molecular determinants shaping the outcome of readthrough, namely the nucleotide and protein context, with the latter being pivotal to produce functional full-length proteins. Through the interpretation of experimental and mechanistic findings, mainly obtained in lysosomal and coagulation disorders, we also propose a scenario of potential readthrough-favorable features to achieve relevant rescue profiles, representing the main issue for the potential translatability of readthrough as a therapeutic strategy. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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36 pages, 2869 KiB

Open AccessReview

Sensing through Non-Sensing Ocular Ion Channels

by Meha Kabra and Bikash Ranjan Pattnaik

Int. J. Mol. Sci. 2020, 21(18), 6925; https://doi.org/10.3390/ijms21186925 - 21 Sep 2020

Cited by 8 | Viewed by 4813

Abstract

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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32 pages, 793 KiB

Open AccessReview

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

by Valentino Bezzerri, Martina Api, Marisole Allegri, Benedetta Fabrizzi, Seth J. Corey and Marco Cipolli

Int. J. Mol. Sci. 2020, 21(13), 4672; https://doi.org/10.3390/ijms21134672 - 30 Jun 2020

Cited by 6 | Viewed by 5285

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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14 pages, 1187 KiB

Open AccessReview

Suppression of Nonsense Mutations by New Emerging Technologies

by Pedro Morais, Hironori Adachi and Yi-Tao Yu

Int. J. Mol. Sci. 2020, 21(12), 4394; https://doi.org/10.3390/ijms21124394 - 20 Jun 2020

Cited by 40 | Viewed by 7104

Abstract

Nonsense mutations often result from single nucleotide substitutions that change a sense codon (coding for an amino acid) to a nonsense or premature termination codon (PTC) within the coding region of a gene. The impact of nonsense mutations is two-fold: (1) the PTC-containing mRNA is degraded by a surveillance pathway called nonsense-mediated mRNA decay (NMD) and (2) protein translation stops prematurely at the PTC codon, and thus no functional full-length protein is produced. As such, nonsense mutations result in a large number of human diseases. Nonsense suppression is a strategy that aims to correct the defects of hundreds of genetic disorders and reverse disease phenotypes and conditions. While most clinical trials have been performed with small molecules, there is an increasing need for sequence-specific repair approaches that are safer and adaptable to personalized medicine. Here, we discuss recent advances in both conventional strategies as well as new technologies. Several of these will soon be tested in clinical trials as nonsense therapies, even if they still have some limitations and challenges to overcome. Full article

(This article belongs to the Special Issue Molecular Approaches Fighting Nonsense)

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