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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    • "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.
    Visual Neuroscience 06/2014; 31(4-5):1-8. DOI:10.1017/S0952523814000194 · 2.21 Impact Factor
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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.
    Human Mutation 03/2014; 35(7). DOI:10.1002/humu.22547 · 5.14 Impact Factor
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    • "This allows translation elongation to continue in the original ribosomal reading frame and results in the production of full-length polypeptide. A number of drugs have been found to stimulate nonsense suppression and restore partial function of deficient proteins associated with a variety of genetic diseases [1]. "
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    ABSTRACT: Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of α-L-iduronidase deficiency. α-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough α-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Iduatm1Kmke MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains α-L-iduronidase activity and GAG reduction in Iduatm1Kmke mice throughout a 28-week treatment period. Examination of more complex MPS I-H phenotypes in Iduatm1Kmke mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease.
    Molecular Genetics and Metabolism 01/2013; 111(2). DOI:10.1016/j.ymgme.2013.12.007 · 2.63 Impact Factor
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