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Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases
1Department 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; kkeeling@uab.edu ; Tel.: +1-205-975-6585.
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.
Insights
Nonsense mutations (premature termination codons) cause genetic diseases by truncating proteins and degrading mRNA. Readthrough therapies and NMD inhibitors offer potential treatments, especially for lysosomal storage diseases.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- Premature termination codons (PTCs), or nonsense mutations, account for about 10% of genetic disease-causing mutations.
- PTCs lead to non-functional truncated proteins and trigger mRNA degradation via nonsense-mediated mRNA decay (NMD).
- Both translation termination and NMD are key therapeutic targets for genetic disorders.
Purpose of the Study:
- To review the therapeutic potential of suppressing PTCs (readthrough) and inhibiting NMD.
- To explore the feasibility of these approaches for treating lysosomal storage diseases.
Main Methods:
- Review of current literature on PTC suppression (readthrough) compounds.
- Review of emerging NMD inhibitors.
- Focus on lysosomal storage diseases as a model for therapeutic intervention.
Main Results:
- Significant progress has been made in identifying compounds that promote readthrough of PTCs.
- NMD inhibitors are being explored to enhance the efficacy of PTC suppression.
- Lysosomal storage diseases present a promising area for investigating nonsense suppression therapies due to their lower correction threshold.
Conclusions:
- PTC suppression and NMD inhibition represent promising therapeutic strategies for genetic diseases.
- These approaches hold particular potential for treating lysosomal storage diseases.
- Further research is warranted to advance these therapies for clinical application.