The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria
The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria
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DOI：
10.1016/j.ymgme.2003.10.002
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发表时间：
2004-01-01
影响因子：
3.8
通讯作者：
Milstien, S
中科院分区：
文献类型：
--
作者：
Harding, CO;Neff, M;Milstien, S
四氢生物蝶呤（BH 4）是苯丙氨酸羟化酶（PAH）酶活性所需的辅因子，在几种组织中由GTP从头合成。PAH在肝脏以外的组织中的异源表达是治疗人苯丙酮尿症的一种潜在的新疗法，其完全依赖于PAH表达组织中的BH 4供应。以前的实验表明，肝脏PAH缺陷转基因小鼠，在骨骼肌中表达PAH的瞬时校正hyperphenylataninernia只有每小时胃肠外BH 4管理。在这份报告中，研究了静脉注射BH 4的结局。结论是：（1）静脉注射BH_4后，肝脏和肾脏迅速摄取BH_4;（2）肌肉摄取BH_4的量相对较低。IV注射后骨骼肌中达到的BH 4水平仅为BH 4自由且均匀分布在所有组织中预期量的10%。BH 4在肌肉中的半衰期约为30分钟，需要重复注射以维持肌肉中足以支持苯丙氨酸羟基化的BH 4含量。异源肌肉定向基因治疗PKU的疗效可能会受到PAH表达肌肉中BH 4供应的限制。(C)2003年爱思唯尔公司All rights reserved.
Tetrahydrobiopterin (BH4) is a required cofactor for the enzymatic activity of phenylalanine, hydroxylase (PAH) and is synthesized de novo from GTP in several tissues. Heterologous expression of PAH in tissues other than liver is a potential novel therapy for human phenylketonuria that is completely dependent upon BH4 supply in the PAH-expressing tissue. Previous experiments with liver PAH-deficient transgenic mice that expressed PAH in skeletal muscle demonstrated transient correction of hyperphenylataninernia only with hourly parenteral BH4 administration. In this report, the fate of intravenously administered BH4 is examined. The conclusions are that (1) BH4 administered intravenously is rapidly taken up by liver and kidney, and (2) uptake of BH4 into muscle is relatively low. The levels of BH4 achieved in skeletal muscle following IV injection are only 10% of the amount expected were BH4 freely and equally distributed across all tissues. The half-life of BH4 in muscle is approximately 30 min, necessitating repeated injections to maintain muscle BH4 content sufficient to support phenylalanine hydroxylation. The efficacy of heterologous muscle-directed gene therapy for the treatment of PKU will likely be limited by the BH4 supply in PAH-expressing muscle. (C) 2003 Elsevier Inc. All rights reserved.