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

Abstract

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.

A structural and functional analysis of opal stop codon translational readthrough during Chikungunya virus replication

“…The biochemical mechanisms underpinning opal stop codon TR remain elusive and require further investigation. In this regard it will be of interest to determine whether new pharmacological interventions that target TR [35] might be of efficacy as novel antiviral agents.…”

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches

“…Ataluren, an oxadiazole discovered to suppress Duchenne muscular dystrophy nonsense mutations, is also renowned [ 28 ]. The mechanisms of action of these nonsense suppressor molecules have been described to some extent [ 29 , 30 ]. For example, Ng et al proposed PTC readthrough orthogonal mechanisms for both ataluren and G418.…”

Stops making sense – For the people?

“…Researchers have been trying to induce SC-RT on PTCs by either increasing the incorporation rates of nc-tRNAs and/or lowering translational accuracy using various read-through-inducing drugs (RTIDs) (for review see Ref. [ 10 ]). One class of RTIDs encompasses notorious aminoglycoside antibiotics, which directly bind to the ribosomal decoding centre and facilitate nc-tRNA mispairing, thereby impairing translational accuracy.…”