Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases

• Published in: Wiley interdisciplinary reviews. RNA Vol. 2; no. 6; p. 837
• Main Authors: Keeling, Kim M, Bedwell, David M
• Format: Journal Article
• Language: English
• Published: United States 01.11.2011
• Subjects: Aminoglycosides - chemistry; Aminoglycosides - pharmacology; Aminoglycosides - toxicity; Animals; Codon, Nonsense - drug effects; Codon, Nonsense - genetics; Codon, Nonsense - metabolism; Drug Design; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - metabolism; Genetic Diseases, Inborn - therapy; Genetic Therapy - methods; Humans; Models, Biological; Models, Genetic; Nonsense Mediated mRNA Decay - drug effects; Peptide Chain Termination, Translational - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Suppression, Genetic
• ISSN: 1757-7012
• DOI: 10.1002/wrna.95

Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy.