The novel aminoglycoside, ELX-02, permits CTNS.sup.W138X translational read-through and restores lysosomal cystine efflux in cystinosis

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 o...

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Published in:PloS one 2019-12, Vol.14 (12), p.e0223954
Main Authors: Brasell, Emma J, Chu, Lee Lee, Akpa, Murielle M, Eshkar-Oren, Idit, Alroy, Iris, Corsini, Rachel, Gilfix, Brian M, Yamanaka, Yojiro, Huertas, Pedro, Goodyer, Paul
Format: Article
Language:English
Subjects:
Aminoglycosides
Cells (Biology)
Cysteine
Cystine
Cystinosis
EDTA
Genes
Genetic aspects
Kidney transplantation
Organ transplantation
Toxicity
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Summary: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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0223954