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Published on: February 4, 2021
Mechanism and evidence of nonsense suppression therapy for genetic eye disorders
Rose Richardson1, Matthew Smart1, Dhani Tracey-White1
1Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, UK.
Abstract:
Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner. This approach aims to suppress the fidelity of the ribosome during protein synthesis so that a near-cognate aminoacyl-tRNA, which shares two of the three nucleotides of the PTC, can be inserted into the peptide chain, allowing translation to continue, and a full-length functional protein to be produced. Here we discuss the mechanisms and evidence of nonsense suppression agents, including the small molecule drug ataluren (or PTC124) and next generation 'designer' aminoglycosides, for the treatment of genetic eye disease.
Insights
Nonsense mutations cause genetic diseases by creating premature stop codons. Nonsense suppression therapies, like ataluren, can restore full-length protein production for treating genetic eye diseases.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- Genetic diseases, including 5-70% of all cases, arise from in-frame nonsense mutations that introduce premature termination codons (PTCs).
- These PTCs lead to the production of truncated, non-functional, or gain-of-function proteins, contributing to disease pathology.
- Approximately 50% of inherited retinal disorders are linked to PTCs, underscoring the need for effective therapies.
Purpose of the Study:
- To explore pharmacological nonsense suppression as a gene- and disease-independent therapeutic strategy for genetic disorders.
- To discuss the mechanisms and evidence supporting nonsense suppression agents for treating genetic eye diseases.
Main Methods:
- Investigating the mechanism of nonsense suppression, which involves promoting the ribosome to insert a near-cognate aminoacyl-tRNA at the PTC.
- Reviewing evidence for small molecule drugs like ataluren (PTC124) and advanced 'designer' aminoglycosides as therapeutic agents.
Main Results:
- Nonsense suppression enables the ribosome to bypass PTCs, facilitating the synthesis of full-length, functional proteins.
- Evidence supports the potential of ataluren and designer aminoglycosides in counteracting the effects of nonsense mutations.
Conclusions:
- Pharmacological nonsense suppression offers a promising therapeutic avenue for genetic diseases caused by PTCs.
- This approach holds significant potential for treating a range of genetic eye conditions by restoring protein function.
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