Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice
Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice
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DOI：
10.1038/sj.gt.3302262
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发表时间：
2004-07-01
期刊：
影响因子：
5.1
通讯作者：
Kume, A
中科院分区：
文献类型：
--
作者：
Mochizuki, S;Mizukami, H;Kume, A
经典型的苯丙酮尿症(PKU)是由肝酶苯丙氨酸羟基酶(PAH)缺乏引起的一种代谢紊乱。如果不治疗，苯丙氨酸的积累将损害受影响个人的发育中的大脑，导致严重的精神发育迟滞。在这里，我们证明了肝脏导向的PAH基因转移带来了高苯丙氨酸血症的长期纠正和PKU小鼠模型的行为改善。构建了携带小鼠PAH基因的重组腺相关病毒(AAV)载体，经门静脉注射给PAH基因缺陷小鼠(PAH(Enu2)株)。在治疗的2周内，接受更高剂量载体治疗的动物的高苯丙氨酸血症表型得到改善并完全恢复正常。这种治疗效果在雄性小鼠身上持续了40周，而雌性动物的血清苯丙氨酸浓度逐渐恢复到治疗前的水平。值得注意的是，这种对高苯丙氨酸血症的长期纠正与PAH(Enu2)小鼠观察到的低活动状态的逆转有关。与年龄匹配的对照组相比，未经治疗的PAHenu2组小鼠24小时以上的活动能力和探索行为显著降低，而12月龄雄性PKU小鼠的这些指标完全正常化，同时血清苯丙氨酸水平降低。这些结果表明，AAV介导的肝转导可以改善PKU表型，包括中枢神经系统功能障碍。
Classical phenylketonuria (PKU) is a metabolic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If untreated, accumulation of phenylalanine will damage the developing brain of affected individuals, leading to severe mental retardation. Here, we show that a liver-directed PAH gene transfer brought about long-term correction of hyperphenylalaninmia and behavioral improvement in a mouse model of PKU. A recombinant adeno-associated virus (AAV) vector carrying the murine PAH cDNA was constructed and administered to PAH-deficient mice ( strain PAH(enu2)) via the portal vein. Within 2 weeks of treatment, the hyperphenylalaninemic phenotype improved and completely normalized in the animals treated with higher vector doses. The therapeutic effect persisted for 40 weeks in male mice, while serum phenylalanine concentrations in female animals gradually returned to pretreatment levels. Notably, this long-term correction of hyperphenylalaninemia was associated with a reversal of hypoactivity observed in PAH(enu2) mice. While locomotory activity over 24 h and exploratory behavior were significantly decreased in untreated PAHenu2 mice compared with the age-matched controls, these indices were completely normalized in 12-month- old male PKU mice with lowered serum phenylalanine. These results demonstrate that AAV-mediated liver transduction ameliorated the PKU phenotype, including central nervous system dysfunctions.