Patejunas G, Lee B, Dennis J A, Healy P J, Reeds P J, Yu H, Frazer M, Mull B, Warman A W, Beaudet A L, O'Brien W E
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
J Inherit Metab Dis. 1998;21 Suppl 1:138-50. doi: 10.1023/a:1005322010854.
Citrullinaemia is an autosomal recessive disorder caused by the deficiency of argininosuccinate synthase. The deficiency of this enzyme results in an interruption in the urea cycle and the inability to dispose of excess ammonia derived from the metabolism of protein. The only treatment for this disorder has been dietary restriction of protein and supplementation with medications allowing for alternative excretion of excess nitrogen. Gene therapy offers the possibility of a long-term cure 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 naturally occurring bovine model and a murine model created by molecular mutagenesis. Mice treated with adenoviral vectors expressing argininosuccinate 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 deficiency of arginine. In the bovine model, the use of adenoviral vectors did not result in any change in the clinical condition of the animals or in the level of plasma ammonia. However, the use of 15N isotopic ammonia allowed us to assess the flux of nitrogen through the urea cycle during the experiment. These studies revealed a significant increase in the flux through the urea cycle following administration of adenoviral 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 designed to address these issues.
瓜氨酸血症是一种由精氨琥珀酸合成酶缺乏引起的常染色体隐性疾病。这种酶的缺乏导致尿素循环中断，无法处理蛋白质代谢产生的过量氨。这种疾病的唯一治疗方法是限制蛋白质饮食并补充药物以允许过量氮的替代排泄。基因治疗通过在靶器官中表达缺陷基因，为治疗瓜氨酸血症等疾病提供了长期治愈的可能性。我们在两种动物模型中探索了使用腺病毒载体作为瓜氨酸血症的治疗方式，一种是自然发生的牛模型，另一种是通过分子诱变创建的小鼠模型。用表达精氨琥珀酸合成酶的腺病毒载体治疗的小鼠比未治疗的动物存活时间显著延长（11天对1天）；然而，动物在实验期间体重没有正常增加，表明转导病毒的治疗效果次优。据推测，未能观察到更好临床结果的部分原因可能是精氨酸缺乏。在牛模型中，使用腺病毒载体并未导致动物临床状况或血浆氨水平发生任何变化。然而，使用15N同位素氨使我们能够在实验期间评估氮通过尿素循环的通量。这些研究表明，在给予表达精氨琥珀酸合成酶的腺病毒载体后，通过尿素循环的通量显著增加。我们得出结论，使用腺病毒载体治疗瓜氨酸血症是一种可行的治疗方法，但有必要提高转导水平并提高重组病毒载体产生的酶水平。未来的实验将设计用于解决这些问题。
