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



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.


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


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