The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy

Scientific Reports
Simona TorrianoVasiliki Kalatzis

Abstract

Inherited retinal dystrophies (IRDs) are caused by mutations in over 200 genes, resulting in a range of therapeutic options. Translational read-through inducing drugs (TRIDs) offer the possibility of treating multiple IRDs regardless of the causative gene. TRIDs promote ribosomal misreading of premature stop codons, which results in the incorporation of a near-cognate amino acid to produce a full-length protein. The IRD choroideremia (CHM) is a pertinent candidate for TRID therapy, as nonsense variants cause 30% of cases. Recently, treatment of the UAA nonsense-carrying CHM zebrafish model with the TRID PTC124 corrected the underlying biochemical defect and improved retinal phenotype. To be clinically relevant, we studied PTC124 efficiency in UAA nonsense-carrying human fibroblasts and induced pluripotent stem cell-derived retinal pigment epithelium, as well as in a UAA-mutated CHM overexpression system. We showed that PTC124 treatment induces a non-significant trend for functional rescue, which could not be improved by nonsense-mediated decay inhibition. Furthermore, it does not produce a detectable CHM-encoded protein even when coupled with a proteasome inhibitor. We suggest that drug efficiency may depend upon on the target ...Continue Reading

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Citations

Mar 21, 2020·Pharmacology Research & Perspectives·Ronald KongElizabeth Goodwin
Dec 14, 2018·Orphanet Journal of Rare Diseases·Anna Skorczyk-WernerMaciej Robert Krawczynski
Jan 11, 2019·Therapeutic Advances in Ophthalmology·Andreas MitsiosMariya Moosajee
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Methods Mentioned

BETA
biopsy
Flow cytometry
PCR
FCS
flow

Clinical Trials Mentioned

NCT02139306
NCT01826487
NCT02647359

Software Mentioned

PROVEAN
PolyPhen
Image J
2 HumVar
SIFT
Excel
PyMOL Molecular Graphics System
MutationAssessor
PMut
SNAP

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