Pathogenic nonsense variants introduce premature termination codons (PTCs) into gene coding sequences, resulting in truncated, typically nonfunctional proteins. Translational readthrough has emerged as a promising therapeutic strategy for genetic diseases caused by nonsense variants. Small molecules, known as translational readthrough-inducing drugs (TRIDs), act as therapeutic agents, by allowing the translation machinery to suppress nonsense variants. TRIDs induce ribosomes to bypass aberrant stop codons favoring the incorporation of near-cognate amino acids at PTC sites. This restores the synthesis of full-length, potentially functional proteins. As TRIDs function on the mRNA level, they enable the expression of various heterogeneous isoforms of the target gene, and moreover the size of the gene is not relevant. This paves the way for the treatment of patients carrying PTCs in genes with many splice variants and in large genes. Although the efficacy of TRIDs varies across genes and PTCs, one TRID could potentially be applied for different disease-causing genes, making the strategy particularly attractive from an economic perspective for rare and ultra-rare disorders. Here we describe basic aspects of translational readthrough, TRIDs currently under investigation for the treatment of Inherited Retinal Disorders and discuss the current needs to improve translational readthrough therapy. Finally, we describe a "pipeline" to identify the best TRIDs for a specific gene/PTC, which could provide a customized readthrough approach for each patient with a PTC-caused disease.
Nagel-Wolfrum et al. (Thu,) studied this question.