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Abstract: FR-PO322

Investigational Therapy of Alport Syndrome With ELX-02

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Badarinarayana, Vasudeo, Eloxx Pharmaceuticals Inc., Watertown, Massachusetts, United States
  • Omachi, Kohei, Washington University in St Louis, St Louis, Missouri, United States
  • Cox, Megan K., Eloxx Pharmaceuticals Inc., Watertown, Massachusetts, United States
  • Hariri, Ali, Eloxx Pharmaceuticals Inc., Watertown, Massachusetts, United States
  • Miner, Jeffrey H., Washington University in St Louis, St Louis, Missouri, United States
  • Modur, Vijay, Eloxx Pharmaceuticals Inc., Watertown, Massachusetts, United States

Alport syndrome is a genetic disease caused by mutations in COL4A3, COL4A4 and COL4A5 genes leading to glomerular fragility, hematuria and proteinuria resulting in ESRD early in life. The most frequent form is X-linked Alport syndrome, which is caused by mutations in COL4A5. ELX-02 is an aminoglycoside analog specifically designed to readthrough premature termination (nonsense) codon mutations and produce full-length proteins instead of truncated proteins. We show here the potential for ELX-02 as an investigational therapy in Alport Syndrome.


: A list of nonsense mutations in COL4A5 associated with Alport syndrome was compiled from ClinVar, LOVD, Ensemble and deafness variation database. The number of unique nonsense mutations and frequency of each were determined. Type of nonsense codon (UGA, UAG or UAA) was derived from sequence variant. 13 of the mutants were selected for analysis by dual reporter assay for responsiveness to ELX-02 induced readthrough. To assess expected clinical exposure in kidney for ELX-02, a Physiologically Based Pharmacokinetic (PBPK) model was built based on preclinical pharmacokinetic data from mouse, rat and dog studies using Gastroplus simulation software.


Analysis of reported nonsense mutations compiled across different variant databases showed approximately 6% of reported pathogenic mutations in COL4A5 are of the nonsense subtype. Dual reporter assays were designed for 13 of these mutations to test for responsiveness to ELX-02. All the tested mutations had >3-fold increase in readthrough with an average of XX-Fold. PBPK modeling showed that ELX-02 levels in the kidney are >50-fold greater than plasma levels across a range of doses suggesting high exposures in the kidneys even at 0.71 mg/kg dose.


The promise of this investigational therapy in Alport syndrome is supported by several lines of evidence. 1) Nonsense mutations in COL4A5 are a significant cause of Alport Syndrome. 2) ELX-02 shows nonsense mutation readthrough across a range of nonsense mutations in Alport Syndrome. 3) PBPK modeling shows high levels of ELX-02 exposures can be achieved in the kidneys even at doses below those currently being used in clinical trials.


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