Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond

• Published in: International journal of molecular sciences 2023-03, Vol.24 (7), p.6101
• Main Authors: Wagner, Roland N, Wießner, Michael, Friedrich, Andreas, Zandanell, Johanna, Breitenbach-Koller, Hannelore, Bauer, Johann W
• Format: Article
• Language: English
• Subjects: Accuracy; Amino acids; Aminoglycoside antibiotics; Aminoglycosides; Aminoglycosides - pharmacology; Animals; Antibiotics; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Clinical trials; Codon; Codon, Nonsense - genetics; Codons; Customization; Cystic Fibrosis - genetics; Cystic Fibrosis - therapy; Drugs; Epidermolysis bullosa; epidermolysis bullosa (EB); Epidermolysis Bullosa - genetics; Epidermolysis Bullosa - therapy; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - therapy; Genetic disorders; Genetic research; Genetic translation; Health services; Humans; Localization; Medical research; Medicine, Experimental; Mutation; Nephritis, Hereditary - genetics; Nephritis, Hereditary - therapy; Nonsense Mediated mRNA Decay; nonsense suppression therapy; Peptide Chain Elongation, Translational - drug effects; Peptide Chain Termination, Translational - drug effects; Physiology; Precision Medicine - methods; Precision Medicine - trends; premature termination codon (PTC); Proteins; Rare diseases; Rare Diseases - genetics; Rare Diseases - therapy; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - therapy; Review; Shwachman-Diamond Syndrome - genetics; Shwachman-Diamond Syndrome - therapy; Stop codon; Suppression, Genetic - drug effects; Suppression, Genetic - genetics; Translation; Translation termination; translational readthrough
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076101

Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.