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The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis

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 Joles, Jaap A.

PloS one, 2019-12, Vol.14 (12), p.e0223954-e0223954 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis
Autor: 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
Joles, Jaap A.
Assuntos: Accumulation ; Age ; Amino Acid Transport Systems, Neutral - physiology ; Aminoglycosides ; Aminoglycosides - pharmacology ; Animals ; Antibiotics ; Autophagy ; Biocompatibility ; Biological Transport ; Biology and Life Sciences ; Cysteamine ; Cystine ; Cystine - metabolism ; Cystinosis ; Cystinosis - drug therapy ; Cystinosis - metabolism ; Cystinosis - pathology ; Cytotoxicity ; Efflux ; Fanconi syndrome ; Female ; Gene expression ; Genetics ; Hemodialysis ; Hereditary diseases ; Inner ear ; Kidney transplantation ; Kidneys ; Lysosomes - metabolism ; Male ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Nephrology ; Nonsense mutation ; Protein Biosynthesis ; Protein synthesis ; Proteins ; Research and Analysis Methods ; Toxicity ; Transcription ; Translation ; Transplants & implants
É parte de: PloS one, 2019-12, Vol.14 (12), p.e0223954-e0223954
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Current address: The Research Institute of the McGill university Health Centre, Montreal, Quebec, Canada
Competing Interests: Dr. Goodyer was the recipient of an unrestricted grant from Eloxx Pharmaceuticals, Inc. for parts of this work. RIMUHC-affiliated authors were not Eloxx employees nor did they have any commercial affiliation or patent interests related to ELX-02. Idit Eshkar-Oren, Iris Alroy and Pedro Huertas were employees of Eloxx Pharmaceuticals, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis

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 Joles, Jaap A.

United States: Public Library of Science

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