Article

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: 7.75). 07/2012; 136(2):227-66. DOI: 10.1016/j.pharmthera.2012.07.007
Source: PubMed

ABSTRACT 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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    • "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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    • "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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