Quantitative Measurement of Phenylalanine Metabolism in Sapropterin-Responsive Hyperphenylalaninemia

5.项目总结--项目2 本项目的目标是验证非侵入性测量全身苯丙氨酸(Phe)的方法。 苯丙氨酸羟基酶个体中不受膳食苯丙氨酸摄入量影响的代谢率 (PAH)缺乏。未来肝脏导向基因治疗PAH缺乏症的临床试验将 要求使用这种方法来衡量治疗效果。我们建议评估两种不同的方法 测量苯丙氨酸代谢：1)测量口服后随时间呼气中13CO2的增加 注射1-13C-L-苯丙氨酸；2)测定血浆苯丙氨酸清除率和血浆酪氨酸 禁食状态下口服无标记苯丙氨酸后的生产。这些措施将反复实施。 在完全或部分PAH缺乏的同一研究对象队列中的时间，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 非侵入性测量苯丙氨酸代谢的测试方法和准备临床试验准备方案 未来的用途。

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.