Abstract
We have achieved significant improvement of ornithine transcarbamylase deficiency (OTCD) in a mouse model through adenoviral-mediated gene transfer of the human ornithine transcarbamylase cDNA. Substantial reduction in orotic aciduria was observed within 24 h of treatment. Metabolic correction was later associated with phenotypic correction and moderate increase in enzymatic activity. In an effort to identify the level of gene expression required to achieve wild-type levels of enzyme activity we uncovered a dominant negative effect of the endogenous mutant protein on the activity of the delivered recombinant wild-type protein. This phenomenon is relevant to homomultimeric protein defects such as OTCD, represent a challenging category of disorders for gene therapy. Thus, although our findings indicate that adenoviral-mediated gene transfer may have potential as a short-term treatment for OTCD in humans and may be effective especially during catabolic crisis, the observations in this study suggest that careful patient selection based on mutation class may be essential for initial OTCD gene therapy trials, and perhaps, for other homomultimeric enzyme deficiencies being considered as gene therapy targets.
References
May 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·R DeMarsL B Russell
Jul 1, 1979·Pediatric Research·I A QureshiR Ouellet
Jul 1, 1977·The Journal of General Virology·F L GrahamR Nairn
May 7, 1976·Analytical Biochemistry·M M Bradford
Feb 1, 1992·Human Gene Therapy·M GrompeC T Caskey
Dec 1, 1991·The Journal of Pediatrics·N E MaestriS W Brusilow
Jan 1, 1991·American Journal of Medical Genetics·I MatsudaM Yoshino
Jan 1, 1990·Human Gene Therapy·L D Stratford-PerricaudetP Briand
Jun 7, 1990·The New England Journal of Medicine·P H ArnS W Brusilow
Jun 1, 1990·Genomics·J E FinkelsteinM D Traystman
Jun 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·P E Hodges, L E Rosenberg
Sep 1, 1989·The Journal of Pediatrics·C LargillièreJ P Farriaux
Apr 29, 1986·Biochemical and Biophysical Research Communications·K W VolźW N Lipscomb
Jan 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·S R Wente, H K Schachman
Feb 1, 1986·The Journal of Pediatrics·M L BatshawJ Trojak
Feb 27, 1986·The New England Journal of Medicine·P C RoweS W Brusilow
Feb 15, 1968·Experientia·A StajnerF Musil
Jul 20, 1981·FEBS Letters·P BriandM Penninckx
May 1, 1995·Journal of Cellular Biochemistry·P A Gruppuso, J M Boylan
Sep 1, 1993·The Journal of Clinical Investigation·M A MorsyC T Caskey
Citations
Dec 24, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·J P SchofieldM Wakamiya
Oct 22, 2003·Molecular Genetics and Metabolism·Steven E RaperMark L Batshaw
Apr 10, 2009·Gene Therapy·S L GinnI E Alexander
Jul 8, 1998·Proceedings of the National Academy of Sciences of the United States of America·M A MorsyC T Caskey
Jan 10, 2002·Human Gene Therapy·Steven E RaperMark L Batshaw
Jun 12, 2001·Human Gene Therapy·X YeM B Robinson
Jun 18, 2002·Human Gene Therapy·Taizo WadaFabio Candotti
May 26, 1998·Annals of the New York Academy of Sciences·B C O'ConnellD Kruse
Apr 1, 1997·Pediatric Research·X YeM L Batshaw
Dec 5, 2000·Pediatric Research·L AugustinM Tuchman
Dec 3, 2011·Molecular Genetics and Metabolism·Lili WangJames M Wilson
Oct 16, 2007·Molecular Genetics and Metabolism·Joshua L DeignanWayne W Grody
Aug 18, 2005·Biochemical and Biophysical Research Communications·N KuwadaE R B McCabe
Sep 1, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Asad MianBrendan Lee
Jun 1, 1997·Human Molecular Genetics·H MorizonoM Tuchman
Feb 7, 2003·Gene Therapy·E VigneP Yeh
Mar 10, 2001·Blood·M OtsuF Candotti
Aug 1, 1998·Journal of Inherited Metabolic Disease·M TuchmanN M Allewell
Aug 1, 1998·Journal of Inherited Metabolic Disease·S E RaperM L Batshaw
Aug 1, 1998·Journal of Inherited Metabolic Disease·G PatejunasW E O'Brien
May 26, 2021·Epilepsia Open·Aristea S GalanopoulouBrian Klein