AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice

Mol Genet Metab. 2017 Apr;120(4):299-305. doi: 10.1016/j.ymgme.2017.02.011. Epub 2017 Mar 2.


Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder of the urea cycle. Hemizygous males and heterozygous females may experience life-threatening elevations of ammonia in blood and brain, leading to irreversible cognitive impairment, coma, and death. Recent evidence of acute liver failure and fibrosis/cirrhosis is also emerging in OTC-deficient patients. Here, we investigated the long-term consequences of abnormal ureagenesis in female mice heterozygous (Het) for a null mutation in the OTC gene. Two-month-old Het OTC knockout (KO) mice received a single dose of self-complementary adeno-associated virus (AAV) encoding a codon-optimized human OTC gene at 1×1010, 3×1010, or 1×1011 vector genome copies per mouse. We compared liver pathology from 18-month-old treated Het OTC-KO mice, age-matched untreated Het OTC-KO mice, and WT littermates, and assessed urinary orotic acid levels and vector genome copies in liver at 4, 10, and 16months following vector administration. Het OTC-KO female mice showed evidence of liver inflammation and the eventual development of significant fibrosis. Treatment with AAV gene therapy not only corrected the underlying metabolic abnormalities, but also prevented the development of liver fibrosis. Our study demonstrates that early treatment of OTC deficiency with gene therapy may prevent clinically relevant consequences of chronic liver damage from developing.

Keywords: AAV; Gene therapy; Liver fibrosis; OTC deficiency.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Genetic Vectors / administration & dosage*
  • Humans
  • Liver Cirrhosis / prevention & control*
  • Male
  • Mice
  • Mice, Knockout
  • Ornithine Carbamoyltransferase / genetics*
  • Ornithine Carbamoyltransferase Deficiency Disease / complications
  • Ornithine Carbamoyltransferase Deficiency Disease / genetics
  • Ornithine Carbamoyltransferase Deficiency Disease / therapy*
  • Treatment Outcome


  • Ornithine Carbamoyltransferase