THE SPARSE FUR MOUSE AS A MODEL FOR GENE-THERAPY IN ORNITHINE CARBAMOYLTRANSFERASE DEFICIENCY

The sparse fur (spf/Y) mouse was valuated as a model for studying gene therapy in ornithine carbamoyltransferase transferase deficiency (OCT D), the most common inborn error of urea synthesis. Previous studies h ave defined a number of biochemical characteristics of this animal mod el that are analogous to the human disease: OCTD in liver, elevated am monium and glutamine, low citrulline and arginine in plasma, elevated urinary erotic acid excretion, neurochemical alterations and responsiv eness to alternative pathway therapy. in this study, metabolic flux, s urvival, behavior and learning of these animals were examined in prepa ration for a trial of gene therapy. We found that as has been previous ly reported, OCT activity in liver ranged from 10 to 20% of control. Y et, stable isotope studies using N-15 ammonium chloride to follow urea genesis in vivo showed 55% of normal urea synthetic capacity. This sug gests that partial correction with gene therapy may be sufficient to n ormalize urea synthesis. Although it has been suggested that liver OCT D and its consequent metabolic effects normalize without treatment by adulthood in the spf/Y mouse, we did not find this to be the case. We documented that the spf/Y mouse had a markedly decreased lifespan (<10 % of normal) and remained runted throughout life. In terms of behavior , the spf/Y mice had evidence of decreased learning in a passive avoid ance task that was not attributable to alterations in activity. These clearly definable metabolic and behavioral abnormalities suggest that the spf/Y mouse should prove a useful model for studying the efficacy of gene therapy in OCTD.