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Kidney Week

Abstract: TH-PO813

Cystinosis Nonsense Mutation Read-Through Mediated by ELX-02 Restores Protein Function Using In Vitro and In Vivo Models

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Goddeeris, Matthew, Eloxx Pharmaceuticals, Inc, Waltham, Massachusetts, United States
  • Williams, Gregory, Eloxx Pharmaceuticals, Inc, Waltham, Massachusetts, United States

Cystinosis is a rare disorder caused by mutations of the cysinosin (CTNS) gene. Approximately 15% of cystinosis patients worldwide carry one or more nonsense mutations which halt translation of the CTNS protein through introduction of a premature stop codon. ELX-02 is an investigational synthetic eukaryotic ribosomal selective glycoside that induces read-through of nonsense mutations through interaction with the ribosome resulting in full-length functional proteins. ELX-02 is being developed as a therapy for genetic diseases caused by nonsense mutations such as nephropathic cystinosis and polycystic kidney disease.


This study evaluated the effects of ELX-02 on fibroblasts from patients with cystinosis homozygous for W138X mutation, as well as ELX-02 effects on mouse models of cystinosis with a Y226X mutation.


In cystinosis patients' fibroblasts homozygous for the nonsense W138X mutation incubation of ELX-02 at escalating dose for 72 hours resulted in reduced half-cystine levels (at ≥100 μg/mL) up to normal levels, and significantly increased CTNS mRNA levels (at ≥200 μg/mL) by 2.5- to 3.5-fold. Treatment of compound heterozygous cystinosis patient human fibroblasts, CTNSW138X/57kbDel and CTNSW138X/Frameshift mutations, with ELX-02 resulted in increased CTNS mRNA levels and a trend in reduction of half-cystine levels. In a mouse model of cystinosis bearing a Y226X mutation, the PK of ELX-02 in plasma and kidneys and the renal half-cystine levels were evaluated following single and repeated bi-weekly subcutaneous administration of ELX-02 at 9 mg/kg for up to 21 days. Cystine levels decreased by 30% compared to control animals.


The pharmacodynamic effect of ELX-02 treatment on cystine levels suggests that ELX-02 induced functional read-through of cystinosin and demonstrated that the expressed protein reduced the accumulated lysosomal cystine by one third in the time frame of the experiment at the given dose. These results support the continued development of ELX-02 for the potential treatment of nephropathic cystinosis and other nonsense mutation mediated diseases of the kidney.


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