Quantitative Measurement of Phenylalanine Metabolism in Sapropterin-Responsive Hyperphenylalaninemia

5.项目概要-项目2 该项目的目的是验证测量全身苯丙氨酸（Phe）的非侵入性方法 苯丙氨酸羟化酶患者的代谢率不受膳食苯丙氨酸摄入量的干扰 (PAH)缺陷未来肝脏定向基因治疗PAH缺乏症的临床试验将 需要使用这些方法来测量治疗效果。我们建议评估两种不同的方法 测量Phe代谢的方法：1）在口服后随时间测量呼吸中的13 CO2富集 施用1- 13 C-L-苯丙氨酸，和2）测量血浆Phe清除率和血浆酪氨酸 在禁食状态下口服未标记的Phe攻击后的生产。这些措施将重复实施 完全或部分PAH缺乏的同一研究受试者队列中的时间，以评估敏感性 和方法的重测变异性。该项目将评估拟议的敏感性和稳定性， 非侵入性地测量Phe代谢的测试方法，并准备临床试验准备方案， 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.