Toward Altered Probiotic Therapy for Phenylketonuria

摘要 PKU对婴儿和成人的严重急性和慢性发育和神经影响是 由于血液中存在高浓度的苯丙氨酸(Phe)。在患有PKU的孕妇中， 苯丙氨酸水平过高会显著增加流产或严重发育障碍的风险 胎儿。PKU的不良影响可以通过降低全身Phe水平和各种干预措施来缓解。 (药理的、酶的和饮食相关的)已经尝试过，并取得了一些成功。这项工作是基于 这一假说认为，由利用苯丙氨酸为底物的益生菌提供的高活性酶可以重新- 引导其流量远离肠道顶端氨基酸转运体，从而最大限度地减少苯丙氨酸在肠道中的吸收 直觉。这项工作的长期目标是开发这种改变的益生菌疗法(APT)方法来治疗 北京大学的治疗。这项提案的目标是设计一种益生菌的活性，使其能够 治疗苯丙氨酸解氨酶(PAL)对肠道和增强滞留时间的有效 Phe耗尽。APT方法可以提供一种新的和整体的方法来治疗各种与Phe相关的疾病 代谢紊乱包括PKU、母体PKU和高苯丙氨酸血症(HPA)。

Summary The severe acute and chronic developmental and neurological impacts of PKU seen in infants and adults are due to the presence of high concentrations of phenylalanine (Phe) in the blood. In pregnant mothers with PKU, high Phe levels significantly increase the risk of miscarriage or severe developmental disorders in the growing fetus. The adverse effects of PKU can be alleviated by lowering systemic levels of Phe, and various interventions (pharmacological, enzymatic, and diet-related) have been attempted with some success. This work is based on that hypothesis that highly active enzymes delivered by probiotic bacteria that utilize Phe as substrate can re- direct its flux away from the apical amino acid transporters in the gut and thus minimize Phe absorption in the gut. The long-term goal of this work is to develop this Altered Probiotic Therapy (APT) approach for the treatment of PKU. The objective of this proposal is to engineer the activity of a probiotic organism to deliver therapeutic Phenylalanine Ammonia Lyase (PAL) enzyme to the gut and to enhance residence time for efficient Phe depletion. The APT approach can provide a novel and holistic approach to treating the various Phe-related metabolic disorders including PKU, maternal PKU, and hyperphenylalaninemia (HPA).