Ballantyne Laurel L, Sin Yuan Yan, St Amand Tim, Si Joshua, Goossens Steven, Haenebalcke Lieven, Haigh Jody J, Kyriakopoulou Lianna, Schulze Andreas, Funk Colin D
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Vascular Cell Biology Unit, VIB Inflammation Research Center, Ghent, Belgium; Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Centre, Melbourne, Australia.
PLoS One. 2015 May 4;10(5):e0125967. doi: 10.1371/journal.pone.0125967. eCollection 2015.
Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies.
精氨酸酶-1催化精氨酸转化为鸟氨酸和尿素，这是尿素循环的最后一步，用于从体内清除多余的氨。精氨酸酶-1缺乏会导致小鼠和人类出现高精氨酸血症，前者会产生严重的致命后果，后者则会出现不同程度的进行性神经损伤。在他莫昔芬诱导的精氨酸酶-1缺陷小鼠模型中，小鼠在敲除基因后2周内死于酶缺乏，肝脏中酶的保留量<2%。精氨酸酶-1缺乏的标准临床护理方案（低蛋白饮食、氮清除药物苯丁酸钠、补充鸟氨酸）要么未能延长寿命（鸟氨酸），要么只能轻微延长寿命（低蛋白饮食和药物联合使用时最长延长8天）。当与诱导型精氨酸酶-1敲除小鼠品系杂交时，一种从Rosa26位点表达该酶的条件性、他莫昔芬诱导型精氨酸酶-1转基因小鼠品系适度延长了新生小鼠的寿命，但没有延长4周龄小鼠的寿命。通过腺相关病毒递送（具有强巨细胞病毒-鸡β-肌动蛋白杂交启动子的rh10血清型）递送精氨酸酶-1/增强型绿色荧光融合构建体挽救了约30%的雄性小鼠，使其寿命延长至至少6个月，肝脏中广泛表达并恢复了显著的酶活性。相比之下，由甲状腺素结合球蛋白启动子驱动的AAV8血清型载体导致肝脏表达较弱，在很大程度上未能挽救精氨酸酶-1缺陷小鼠。由于与人类精氨酸酶-1缺乏相比，诱导型精氨酸酶-1缺陷小鼠模型表现出更为严重的表型，这些研究表明，采用基因治疗策略纠正该疾病的各种表现可能是可行的，这为未来的临床研究带来了希望。
