Open AccessThe novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis
Author(s) -
Emma Brasell,
Lee Lee Chu,
Murielle M. Akpa,
Idit Eshkar-Oren,
Iris Alroy,
Rachel Corsini,
Brian M. Gilfix,
Yojiro Yamanaka,
Pedro E. Huertas,
Paul Goodyer
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0223954
Subject(s) - cystinosis , cysteamine , nonsense mutation , cystine , aminoglycoside , nephrotoxicity , chemistry , kidney , pharmacology , biology , missense mutation , mutation , genetics , biochemistry , gene , cysteine , enzyme , antibiotics
Background Cystinosis is a rare disorder caused by recessive mutations of the CTNS gene. Current therapy decreases cystine accumulation, thus slowing organ deterioration without reversing renal Fanconi syndrome or preventing eventual need for a kidney transplant.15-20% of cystinosis patients harbour at least one nonsense mutation in CTNS , leading to premature end of translation of the transcript. Aminoglycosides have been shown to permit translational read-through but have high toxicity level, especially in the kidney and inner ear. ELX-02, a modified aminoglycoside, retains it read-through ability without the toxicity. Methods and findings We ascertained the toxicity of ELX-02 in cells and in mice as well as the effect of ELX-02 on translational read-through of nonsense mutations in cystinotic mice and human cells. ELX-02 was not toxic in vitro or in vivo , and permitted read-through of nonsense mutations in cystinotic mice and human cells. Conclusions ELX-02 has translational read-through activity and produces a functional CTNS protein, as evidenced by reduced cystine accumulation. This reduction is comparable to cysteamine treatment. ELX-02 accumulates in the kidney but neither cytotoxicity nor nephrotoxicity was observed.