The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis
Autoři:
Emma J. Brasell aff001; Lee Lee Chu aff002; Murielle M. Akpa aff002; Idit Eshkar-Oren aff003; Iris Alroy aff003; Rachel Corsini aff002; Brian M. Gilfix aff002; Yojiro Yamanaka aff001; Pedro Huertas aff003; Paul Goodyer aff001
Působiště autorů:
McGill University, Department of Human Genetics, Montreal, Canada
aff001; Research Institute of the McGill University Health Centre, Montreal, Canada
aff002; McGill University, Department of Experimental Medicine, Montreal, Canada
aff003; Montreal Children’s Hospital, Department of Nephrology, Montreal, Canada
aff004; Eloxx Pharmaceuticals, Inc., Waltham, United States of America
aff005
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0223954
Souhrn
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.
Klíčová slova:
Blood – Blood plasma – Fibroblasts – Kidneys – Lysosomes – Mouse models – Nonsense mutation – Toxicity
Zdroje
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