Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome

Mol Genet Metab. 2012 Feb;105(2):203-11. doi: 10.1016/j.ymgme.2011.10.020. Epub 2011 Nov 7.


Ornithine transcarbamylase deficiency (OTCD), the most common and severe urea cycle disorder, is an excellent model for developing liver-directed gene therapy. No curative therapy exists except for liver transplantation which is limited by available donors and carries significant risk of mortality and morbidity. Adeno-associated virus 8 (AAV8) has been shown to be the most efficient vector for liver-directed gene transfer and is currently being evaluated in a clinical trial for treating hemophilia B. In this study, we generated a clinical candidate vector for a proposed OTC gene therapy trial in humans based on a self-complementary AAV8 vector expressing codon-optimized human OTC (hOTCco) under the control of a liver-specific promoter. Codon-optimization dramatically improved the efficacy of OTC gene therapy. Supraphysiological expression levels and activity of hOTC were achieved in adult spf(ash) mice following a single intravenous injection of hOTCco vector. Vector doses as low as 1×10(10) genome copies (GC) achieved robust and sustained correction of the OTCD biomarker orotic aciduria and clinical protection against an ammonia challenge. Functional expression of hOTC in 40% of liver areas was found in mice treated with a low vector dose of 1×10(9) GC. We suggest that the clinical candidate vector we have developed has the potential to achieve therapeutic effects in OTCD patients.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Dependovirus / genetics*
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors*
  • Humans
  • Liver / enzymology
  • Liver / pathology
  • Mice
  • Ornithine Carbamoyltransferase / genetics
  • Ornithine Carbamoyltransferase / metabolism*
  • Ornithine Carbamoyltransferase Deficiency Disease / enzymology
  • Ornithine Carbamoyltransferase Deficiency Disease / genetics*
  • Ornithine Carbamoyltransferase Deficiency Disease / therapy*
  • Orotic Acid / urine


  • Orotic Acid
  • Ornithine Carbamoyltransferase