Quantitative Measurement of Phenylalanine Metabolism in Sapropterin-Responsive Hyperphenylalaninemia

5. 项目摘要——项目 2 该项目的目标是验证测量全身苯丙氨酸 (Phe) 的无创方法 苯丙氨酸羟化酶个体的代谢率不受膳食 Phe 摄入量的影响 （多环芳烃）缺乏。未来用于治疗 PAH 缺乏症的肝脏定向基因疗法的临床试验将 需要使用此类方法来衡量治疗效果。我们建议评估两种不同的方法 测量 Phe 代谢的方法：1) 测量口服后随时间推移呼吸中 13CO2 的富集度 1-13C-L-苯丙氨酸的施用，以及2)血浆Phe清除率和血浆酪氨酸的测量 禁食状态下口服未标记 Phe 挑战后的生产。这些措施将重复实施 在具有完全或部分 PAH 缺乏的同一队列研究受试者中进行时间评估，以评估敏感性 以及方法的重测变异性。该项目将评估拟议的敏感性和稳定性 非侵入性测量 Phe 代谢的测试方法，并准备临床试验方案 未来使用。

5. PROJECT SUMMARY – PROJECT 2 The goal of this project is to validate noninvasive methods of measuring whole body phenylalanine (Phe) metabolism rates that are not confounded by dietary Phe intake in individuals with phenylalanine hydroxylase (PAH) deficiency. Future clinical trials of liver-directed gene therapy for the treatment of PAH deficiency will require the use of such methods to measure treatment efficacy. We propose to evaluate two different methods of measuring Phe metabolism: 1) measurement of 13CO2 enrichment in breath over time following oral administration of 1-13C-L-phenylalanine, and 2) measurement of plasma Phe clearance and plasma tyrosine production following oral unlabeled Phe challenge in a fasting state. These measures will be repeated over time in the same cohort of study subjects with full or partial PAH deficiency in order to assess the sensitivity and test-retest variability of the methods. This project will assess the sensitivity and stability of the proposed testing methods in measuring Phe metabolism non-invasively and prepare a clinical trial ready protocol for future use.