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The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis.
PLoS One 2019; 14(12):e0223954Plos

Abstract

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.

Authors+Show Affiliations

McGill University, Department of Human Genetics, Montreal, Canada.Research Institute of the McGill University Health Centre, Montreal, Canada.Research Institute of the McGill University Health Centre, Montreal, Canada.McGill University, Department of Experimental Medicine, Montreal, Canada.McGill University, Department of Experimental Medicine, Montreal, Canada.Research Institute of the McGill University Health Centre, Montreal, Canada.Research Institute of the McGill University Health Centre, Montreal, Canada.McGill University, Department of Human Genetics, Montreal, Canada.McGill University, Department of Experimental Medicine, Montreal, Canada.McGill University, Department of Human Genetics, Montreal, Canada. Research Institute of the McGill University Health Centre, Montreal, Canada. Montreal Children's Hospital, Department of Nephrology, Montreal, Canada. Eloxx Pharmaceuticals, Inc., Waltham, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31800572

Citation

Brasell, Emma J., et al. "The Novel Aminoglycoside, ELX-02, Permits CTNSW138X Translational Read-through and Restores Lysosomal Cystine Efflux in Cystinosis." PloS One, vol. 14, no. 12, 2019, pp. e0223954.
Brasell EJ, Chu LL, Akpa MM, et al. The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis. PLoS ONE. 2019;14(12):e0223954.
Brasell, E. J., Chu, L. L., Akpa, M. M., Eshkar-Oren, I., Alroy, I., Corsini, R., ... Goodyer, P. (2019). The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis. PloS One, 14(12), pp. e0223954. doi:10.1371/journal.pone.0223954.
Brasell EJ, et al. The Novel Aminoglycoside, ELX-02, Permits CTNSW138X Translational Read-through and Restores Lysosomal Cystine Efflux in Cystinosis. PLoS ONE. 2019;14(12):e0223954. PubMed PMID: 31800572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel aminoglycoside, ELX-02, permits CTNSW138X translational read-through and restores lysosomal cystine efflux in cystinosis. AU - Brasell,Emma J, AU - Chu,Lee Lee, AU - Akpa,Murielle M, AU - Eshkar-Oren,Idit, AU - Alroy,Iris, AU - Corsini,Rachel, AU - Gilfix,Brian M, AU - Yamanaka,Yojiro, AU - Huertas,Pedro, AU - Goodyer,Paul, Y1 - 2019/12/04/ PY - 2019/03/20/received PY - 2019/10/02/accepted PY - 2019/12/5/entrez PY - 2019/12/5/pubmed PY - 2019/12/5/medline SP - e0223954 EP - e0223954 JF - PloS one JO - PLoS ONE VL - 14 IS - 12 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31800572/The_novel_aminoglycoside,_ELX-02,_permits_CTNSW138X_translational_read-through_and_restores_lysosomal_cystine_efflux_in_cystinosis L2 - http://dx.plos.org/10.1371/journal.pone.0223954 DB - PRIME DP - Unbound Medicine ER -