Jung Sung-Chul, Park Joo-Won, Oh Hyun-Jeong, Choi Jin-Ok, Seo Kyung-In, Park Eun-Sook, Park Hae-Young
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea.
J Korean Med Sci. 2008 Oct;23(5):877-83. doi: 10.3346/jkms.2008.23.5.877.
Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU.
苯丙酮尿症（PKU）是一种常染色体隐性遗传代谢紊乱疾病，由苯丙氨酸羟化酶（PAH）缺乏引起。苯丙氨酸的积累会导致严重的智力和精神运动发育迟缓，未得到控制的孕妇患者的胎儿会出现母体苯丙酮尿症综合征。我们之前曾报道过在小鼠模型Pahenu2中，通过2型腺相关病毒（AAV）介导的人类PAH转基因基因递送，实现PKU生化和表型逆转后的认知结果。然而，治疗效果仅限于雄性PKU小鼠。在本研究中，我们构建了一种假型重组AAV2/8-hPAH载体，并通过肝门静脉或尾静脉将其注入雌性PKU小鼠体内。注射两周后，观察到雌性PKU小鼠的毛发颜色完全变为黑色，与雄性小鼠情况相同。雌性PKU小鼠肝脏中的PAH活性增加到野生型活性的65 - 70%，雄性PKU小鼠则增加到90%。雌性PKU小鼠血浆苯丙氨酸浓度降至正常值。此外，经治疗的雌性PKU小鼠的后代能够从母体高苯丙氨酸血症的有害影响中得到挽救。这些结果表明，重组AAV2/8介导的基因治疗是PKU的一种潜在治疗策略。
