G. Patejunas et al., EVALUATION OF GENE-THERAPY FOR CITRULLINEMIA USING MURINE AND BOVINE MODELS, Journal of inherited metabolic disease, 21, 1998, pp. 138-150
Citrullinaemia is an autosomal recessive disorder caused by the defici
ency of argininosuccinate synthase. The deficiency of this enzyme resu
lts In an interruption in the urea cycle and the inability to dispose
of excess ammonia derived from the metabolism of protein. The only tre
atment for this disorder has been dietary restriction of protein and s
upplementation with medications allowing for alternative excretion of
excess nitrogen. Gene therapy offers the possibility of a long-term cu
re for disorders like citrullinaemia by expressing the deficient gene
in the target organ. We have explored the use of adenoviral vectors as
a treatment modality for citrullinaemia in two animal models, a natur
ally occurring bovine model and a murine model created by molecular mu
tagenesis. Mice treated with adenoviral vectors expressing argininosuc
cinate synthase lived significantly longer than untreated animals (11
days vs 1 day; however, the animals did not exhibit normal weight gain
during the experiment, indicating that the therapeutic effectiveness
of the transducing virus was suboptimal. It is speculated that part of
the failure to observe better clinical outcome might be due to the de
ficiency of arginine. In the bovine model, the use of adenoviral vecto
rs did not result in any change in the clinical condition of the anima
ls or in the level of plasma ammonia. However, the use of N-15 isotopi
c ammonia allowed us to assess the flux of nitrogen through the urea c
ycle during the experiment. These studies revealed a significant incre
ase in the Bur through the urea cycle following administration of aden
oviral vectors expressing argininosuccinate synthase. We conclude that
the use of adenoviral vectors in the treatment of citrullinaemia is a
viable approach to therapy but that it will be necessary to increase
the level of transduction and to increase the level of enzyme produced
from the recombinant viral vector. Future experiments will be designe
d to address these issues.