Affiliations: Department of Pediatrics, Division of Metabolism,
University of Zürich, Zürich, Switzerland
Note: [] Corresponding author: Hiu Man Viecelli, Department of
Pediatrics, Division of Metabolism, University of Zürich, Steinwiesstrasse
75, CH-8032 Zürich, Switzerland. Tel.: +41 44 266 7547; Fax: +41 44 266
7310; E-mail: [email protected]
Abstract: Urea cycle disorders (UCDs) are inborn errors of liver metabolism
that often result in hyperammonemia and failure of arginine synthesis due to
the deficiencies of one of the six enzymes or two mitochondrial transporters
involved. Despite current treatment options, including dietary therapy,
stimulation of alternative routes of nitrogen disposal and cell therapies
(hepatocyte and orthotopic liver transplantation), significant morbidity and
mortality still remain. Gene therapy has emerged as an attractive alternative
strategy for providing a definitive cure for patients with metabolic diseases.
Successful phenotype correction in pre- clinical animal models is encouraging
and research effort is increasingly being focused on translation from the
laboratory bench to proof-of-concept human therapy. Gene therapy for UCDs must
target the periportal hepatocytes, as these are the only liver cells that
express all six enzymes required for full ammonia detoxification. This review
explores current efforts to develop and translate liver-directed gene therapy
approaches to UCDs caused by each of the defects of the six enzymes. The
prominent issues that will need to be addressed and overcome for the future
development of clinical trials, including alternatives to mouse mutants and to
vectors that are not necessarily conditioned to rodents are also discussed.
