TY - JOUR
T1 - Readthrough compounds for nonsense mutations
T2 - bridging the translational gap
AU - Spelier, Sacha
AU - van Doorn, Eveline P.M.
AU - van der Ent, Cornelis K.
AU - Beekman, Jeffrey M.
AU - Koppens, Martijn A.J.
N1 - Funding Information:
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.
Funding Information:
This study was supported by the Nederlandse Cystic Fibrosis Stichting (NCFS) HIT-CF3 program and Elisabeth von Freyburg Stichting . We thank Dr Saskia Houwen (rehabilitation physician, Radboud University Medical Center) and Dr Friso Langen (Fletiopharma consultant) for sharing their knowledge and experience in the context of DMD. All illustrations were created with BioRender.com .
Publisher Copyright:
© 2023 The Authors
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - nonsense mutations
KW - nonsense-mediated decay
KW - rare diseases
KW - readthrough
KW - translational gap
UR - http://www.scopus.com/inward/record.url?scp=85148727463&partnerID=8YFLogxK
U2 - 10.1016/j.molmed.2023.01.004
DO - 10.1016/j.molmed.2023.01.004
M3 - Review article
C2 - 36828712
AN - SCOPUS:85148727463
SN - 1471-4914
VL - 29
SP - 297
EP - 314
JO - Trends in molecular medicine
JF - Trends in molecular medicine
IS - 4
ER -