Readthrough compounds for nonsense mutations: bridging the translational gap.

Sacha Spelier, Eveline P M van Doorn, Cornelis K van der Ent, Jeffrey M Beekman, Martijn A J Koppens

Journal: Trends in molecular medicine 2023;29(4):297-314

PMID: 36828712

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Abstract

Approximately 10% of all pathological mutations are nonsense mutations that are responsible for several severe genetic diseases for which no treatment regimens are currently available. The most widespread strategy for treating nonsense mutations is by enhancing ribosomal readthrough of premature termination codons (PTCs) to restore the production of the full-length protein. In the past decade several compounds with readthrough potential have been identified. However, although preclinical results on these compounds are promising, clinical studies have not yielded positive outcomes. We review preclinical and clinical research related to readthrough compounds and characterize factors that contribute to the observed translational gap.

Address: Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584, CT, Utrecht, The Netherlands.; Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands.; Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584, CT, Utrecht, The Netherlands; Center for Living Technologies, Eindhoven-Wageningen-Utrecht Alliance, Utrecht, The Netherlands.; Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584, CT, Utrecht, The Netherlands; Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands. Electronic address: [email protected].

DOI: 10.1016/j.molmed.2023.01.004