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Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases

Department of Biochemistry and Molecular Genetics, Gregory Fleming Cystic Fibrosis Research Center, Comprehensive Arthritis, Musculoskeletal, Bone, and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Academic Editors: Jose A. Sanchez-Alcazar and Luis M. Jiménez
Diseases 2016, 4(4), 32; https://doi.org/10.3390/diseases4040032
Received: 30 August 2016 / Revised: 13 October 2016 / Accepted: 14 October 2016 / Published: 19 October 2016
(This article belongs to the Collection Lysosomal Storage Diseases)
In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs. Over the past decade, significant progress has been made in the identification of compounds with the ability to suppress translation termination of PTCs (also referred to as readthrough). More recently, NMD inhibitors have also been explored as a way to enhance the efficiency of PTC suppression. Due to their relatively low threshold for correction, lysosomal storage diseases are a particularly relevant group of diseases to investigate the feasibility of nonsense suppression as a therapeutic approach. In this review, the current status of PTC suppression and NMD inhibition as potential treatments for lysosomal storage diseases will be discussed. View Full-Text
Keywords: lysosomal storage diseases; nonsense mutation; suppression; premature termination codon; readthrough; nonsense-mediated mRNA decay; translation termination; therapy; treatment lysosomal storage diseases; nonsense mutation; suppression; premature termination codon; readthrough; nonsense-mediated mRNA decay; translation termination; therapy; treatment
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Keeling, K.M. Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases. Diseases 2016, 4, 32.

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