Pharmaceutical therapies to recode nonsense mutations in inherited diseases

Department of Molecular Genetics, Microbiology, and Immunology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, United States.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 07/2012; 136(2):227-66. DOI: 10.1016/j.pharmthera.2012.07.007
Source: PubMed


Nonsense codons, generated from nonsense mutations or frameshifts, contribute significantly to the spectrum of inherited human diseases such as cystic fibrosis, Duchenne muscular dystrophy, hemophilia, spinal muscular atrophy, and many forms of cancer. The presence of a mutant nonsense codon results in premature termination to preclude the synthesis of a full-length protein and leads to aberrations in gene expression. Suppression therapy to recode a premature termination codon with an amino acid allowing readthrough to rescue the production of a full-length protein presents a promising strategy for treatment of patients suffering from debilitating nonsense-mediated disorders. Suppression therapy using aminoglycosides to promote readthrough in vitro have been known since the sixties. Recent progress in the field of recoding via pharmaceuticals has led to the continuous discovery and development of several pharmacological agents with nonsense suppression activities. Here, we review the mechanisms that are involved in discriminating normal versus premature termination codons, the factors involved in readthrough efficiency, the epidemiology of several well-known nonsense-mediated diseases, and the various pharmacological agents (aminoglycoside and non-aminoglycoside compounds) that are currently being employed in nonsense suppression therapy studies. We also discuss how these therapeutic agents can be used to regulate gene expression for gene therapy applications.

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    • "The high dosage and the chronic treatment result in ototoxicity and renal toxicity. Other compounds were developed with different structure from aminoglycosides in order to identify other molecules with the same activity and high safety profiles[57]. PTC124 (Ataluren, now Tranlsarna™) is one of the identified agent, it is an oral nonaminoglycosides drug which has read-through activity with no antibiotic properties. "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options.
    Preview · Article · Oct 2015 · Molecules
    • "In another approach, PTC therapeutics performed two high throughput screens for read-through mediators using a library containing 800,000 small molecules (Welch et al., 2007 ; Lee & Dougherty, 2012 ). Out of initial 3500 candidate hit compounds, the small molecule PTC124 (Ataluren, 3-[5-(2-fl uorophenyl)-[1] [2] [4] oxadiazol-3-yl]benzoic acid) was identifi ed for further investigations (Peltz et al., 2013 ). "
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    ABSTRACT: The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.
    No preview · Article · Jun 2014 · Visual Neuroscience
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    • "One approach that has been gaining prominence is that of using pharmacological agents to promote nonsense suppression or readthrough of PTCs thus enabling re-expression of full-length functional proteins (Bellais, et al., 2010; Nakamura, et al., 2005). The potential of aminoglycosides and non-aminoglycosides as therapeutic tools has been demonstrated in several genetic disorders such as hemophilia, β-thalassemia, and spinal muscular atrophy, but most extensively in Duchenne muscular dystrophy and cystic fibrosis (Lee and Dougherty, 2012). Interestingly, this treatment was successfully applied on an Ataxia-telangiectasia patient with heterozygous nonsense mutation, thereby demonstrating therapeutic ability despite the presence of a nonsense mutation in just one allele (Nakamura, et al., 2011). "
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    ABSTRACT: Kabuki syndrome is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and qPCR identifying 133 KMT2D, 62 never described before, and 4 KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D truncating mutations affects the expression levels of known KMT2D target genes. Finally we hypothesized that the Kabuki syndrome patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this we performed a proof-of-principle study on 14 KMT2D and 2 KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both, KMT2D and KDM6A nonsense mutations, displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2014 · Human Mutation
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