Abstract
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.
Highlights
In-frame premature termination codons (PTCs) comprise ~10% of all disease-associated gene lesions
This therapeutic approach utilizes small molecular compounds that stimulate the insertion of an amino acid at the site of a PTC during mRNA translation. This mechanism suppresses translation termination at a PTC, allowing translation elongation of the mRNA to continue in the original ribosomal reading frame to generate a full-length polypeptide. This mechanism is often referred to as “readthrough.” While PTCs can be formed by various types of gene lesions, it is single nucleotide substitutions that generate in-frame PTCs that are candidates for nonsense suppression since only suppression of in-frame PTCs has the potential of generating normal protein functionality
To address the limitations of traditional aminoglycosides for nonsense suppression therapy, a medicinal chemistry approach has been pursued to design new aminoglycosides with an increased ability to suppress PTCs, while being less toxic. This was accomplished by designing aminoglycosides that bind more efficiently to cytoplasmic ribosomes in order to induce higher levels of PTC suppression, while reducing the affinity of the aminoglycosides for mitochondrial ribosomes, which plays a significant role in aminoglycoside toxicity [66,108,109,110]
Summary
One-third of all disease-associated gene lesions generate a premature termination codon (PTC) within the open reading frame of an mRNA [1]. This therapeutic approach utilizes small molecular compounds that stimulate the insertion of an amino acid at the site of a PTC during mRNA translation This mechanism suppresses translation termination at a PTC, allowing translation elongation of the mRNA to continue in the original ribosomal reading frame to generate a full-length polypeptide. This mechanism is often referred to as “readthrough.” While PTCs can be formed by various types of gene lesions, it is single nucleotide substitutions that generate in-frame PTCs ( known as nonsense mutations) that are candidates for nonsense suppression since only suppression of in-frame PTCs has the potential of generating normal protein functionality. Further development of nonsense suppression therapy offers the potential of a treatment for a subset of patients with a variety of genetic diseases that often have few, if any, available treatments
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