Kidney Week

Abstract: SA-PO585

The Novel, Non-Toxic Nonsense Suppressor Drug, ELX-02, Is Effective in Cystinosis

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Brasell, Emma J., McGill University, Montreal, Quebec, Canada

Emma J. Brasell,

• Chu, Lee lee, RI-MUHC, Montreal, Alberta, Canada

Lee lee Chu,

• Alroy, Iris, Eloxx Pharmaceuticals, Rehovot, Israel

Iris Alroy,

• Eshkar-Oren, Idit, Eloxx Pharmaceuticals, Rehovot, Israel

Idit Eshkar-Oren,

• Shavit, Michal, Eloxx Pharmaceuticals, Rehovot, Israel

Michal Shavit,

• Shohat, Meytal, Eloxx Pharmaceuticals, Rehovot, Israel

Meytal Shohat,

• Huertas, Pedro, Eloxx Pharmaceuticals, Rehovot, Israel

Pedro Huertas,

• Yamanaka, Yojiro, McGill University, Montreal, Quebec, Canada

Yojiro Yamanaka,

• Goodyer, Paul R., McGill University, Montreal, Quebec, Canada

Paul R. Goodyer,

Background

Cystinosis is caused by mutations in the cystinosin (CTNS) gene, encoding a lysosomal membrane transporter responsible for the efflux of cystine. Intralysosomal cystine accumulation drives progressive organ dysfunction in cystinosis. In Quebec, about 50% of patients harbor a W138X nonsense mutation, causing a premature termination codon (PTC) in exon 7. PTCs cause nonsense-mediated decay (NMD) of mutant transcripts and inhibit protein translation. Aminoglycosides have nonsense suppressor activity, which permits translational read-through of PTCs, but are too toxic to be used for therapy. In contrast, the novel compound ELX-02 was safe and generally well-tolerated in humans up to 5mg/kg.

Methods

To test the efficacy of ELX-02, we treated human fibroblasts harboring the W138X mutation and examined CTNS expression and intracellular cystine levels. Using zinc finger nuclease technology, we generated a Ctns^Y226X/Y226X mouse and replicated the in vitro experiments in mouse fibroblasts. Mice were then injected with ELX-02 (10mg/kg s/c X2/week for 22days). Half-cystine levels were assessed in kidneys and pharmacokinetics (PK) studied in plasma and kidney tissue.

Results

After treatment with ELX-02, CTNS mRNA transcript levels in CTNS^W138X/W138X fibroblasts increased to normal levels and intracellular cystine was reduced. These results suggest that ELX-02 reduces NMD of CTNS^W138X transcript and allows production of functional CTNS protein. In addition, ELX-02 had a similar therapeutic effect on the Y226X mutation in mouse fibroblasts. In ELX-02 treated mice, pathologic half-cystine was reduced to 55% of untreated levels. ELX-02 in plasma had similar Cmax (15ug/ml at 15 min), AUC and elimination half-life (~30 min) following single and repeated administration. ELX-02 was more concentrated in kidney (Cmax 40ug/g), with sustained levels of 15ug/g for > 8 hrs.

Conclusion

These data demonstrate read-through activity of ELX-02 on hCTNS W138X and mCtns Y226X mutations, producing sufficient CTNS protein for cystine efflux from lysosomes. Thus, ELX-02 may be an effective therapy for cystinosis caused by PTCs.

Funding

• Commercial Support – Eloxx Pharmaceuticals