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Review
. 2023 Apr;29(4):297-314.
doi: 10.1016/j.molmed.2023.01.004. Epub 2023 Feb 22.

Readthrough compounds for nonsense mutations: bridging the translational gap

Sacha Spelier  1 , Eveline P M van Doorn  2 , Cornelis K van der Ent  1 , Jeffrey M Beekman  3 , Martijn A J Koppens  4
Affiliations
Free article
Review

Readthrough compounds for nonsense mutations: bridging the translational gap

Sacha Spelier et al. Trends Mol Med. 2023 Apr.
Free article

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.

Keywords: nonsense mutations; nonsense-mediated decay; rare diseases; readthrough; translational gap.

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Conflict of interest statement

Declaration of interests J.M.B. reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries, and Galapagos, outside the submitted work. In addition, J.M.B. has a patent related to the FIS assay with royalties paid. C.K.v.d.E. reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV, and Eloxx outside the submitted work. In addition, C.K.v.d.E. has a patent 10006904 with royalties paid. The other authors declare no conflicts of interest.

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