Treatment of Ornithine Transcarbamylase Deficiency via CRISPR-associated Base Editors – PHRT


Treatment of Ornithine Transcarbamylase Deficiency via CRISPR-associated Base Editors

Short Summary

Ornithine transcarbamylase deficiency is a monogenetic liver diseases, for which no cure besides whole liver transplantation is available. The goal of this study is to develop a CRISPR/Cas9 base editor approach to treat this disease.


In the proposed study we aim to improve and assess efficacy and safety of in vivo base editing in the liver. The goal is to collect preclinical data for a trial on base editing therapies in OTCD patients. In work package one, we will develop novel, transient base editor approaches with potentially reduced off-target mutation rates. In work package two, we will study on- and off target editing rates of base editors in the liver of a large animal model (pig).


For OTCD patients, restoration of approximately 10% of the OTC enzyme activity in the liver would be sufficient to cure the disease. We anticipate to develop a bae editor approach that fulfills this requirement, and test it’s efficacy and safety in pigs.


Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder (UCD). It is an inborn error of liver metabolism, where a deficiency of the ornithine transcarbamylase enzyme leads to an accumulation of neurotoxic ammonia in the blood. There is no cure besides whole liver transplantation. Gene editing via targeted nucleases, such as CRISPR/Cas9, has been suggested as an approach to treat this disease. The system generates a site-specific DNA double-stranded break (DSB), which enables precise modification of the locus when repaired by homologous recombination (HR) from ectopic template DNA. However, recent attempts to apply this technology to mouse models of recessive liver disorders have failed, as in postmitotic hepatocytes the HR pathway is inactive and gene correction rates are low. Recently, a novel CRISPR tool, so-called base editors, have been established. Base editors enable direct conversion of C∙G to T∙A base pairs and vice versa via base deamination. They are therefore independent of DNA break formation and HR. When applied to mouse models of monogenetic liver diseases, the technology enabled gene correction rates above 50%.


Prof. Dr. Markus Stoffel

ETH Zürich


  • Gerald Schwank
  • Johannes Häberle
  • Beat Thöny



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