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Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

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Abstract

In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12 % of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.

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Acknowledgments

The authors thank Helen May-Simera for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg-University of Mainz, Johannes-von-Mueller-Weg 6, 55099, Mainz, Germany

    Kerstin Nagel-Wolfrum, Fabian Möller, Inessa Penner & Uwe Wolfrum

  2. Focus Program Translational Neurosciences (FTN), Johannes Gutenberg-University of Mainz, 55122, Mainz, Germany

    Kerstin Nagel-Wolfrum & Uwe Wolfrum

  3. Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel

    Timor Baasov

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  1. Kerstin Nagel-Wolfrum
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  5. Uwe Wolfrum
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Correspondence to Kerstin Nagel-Wolfrum.

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Funding

This work was supported by the BMBF under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, the Deutsche Forschungsgemeinschaft (GRK 1044), European Community FP7/2009/241955 (SYSCILIA), FAUN-Stiftung, Nuremberg, Foundation Fighting Blindness (FFB, TA-NMT-0611-0538-JGU), and by Tistou and Charlotte Kerstan Stiftung.

Conflicts of interest

K. Nagel-Wolfrum, F. Möller, I. Penner, and U. Wolfrum have no conflicts of interest that are directly relevant to the content of this study. T. Baasov holds patents related to the NB compounds (WO/07/113,841; WO2012/066546) and any related intellectual property was licensed by Technion to a third party. Other than this, he has no other relevant affiliations, financial involvement, or financial conflicts related to the subject or materials discussed in this article.

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Nagel-Wolfrum, K., Möller, F., Penner, I. et al. Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs). BioDrugs 30, 49–74 (2016). https://doi.org/10.1007/s40259-016-0157-6

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