Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria

Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pah^enu2/enu2 PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.C565S/p.F18A PAL). In vivo studies with the most therapeutically effective formulation (5 kDa PEG-Av-p.C503S/p.C565S/p.F18A PAL) revealed that this conjugate, given orally, yielded statistically significant (p = 0.0029) and therapeutically relevant reduction (~ 40%) in plasma phenylalanine (Phe) levels. Phe reduction occurred in a dose- and loading-dependent manner; sustained clinically and statistically significant reduction of plasma Phe levels was observed with treatment ranging between 0.3 IU and 9 IU and with more frequent and smaller dosings. Oral PAL therapy could potentially serve as an adjunct therapy, perhaps with dietary treatment, and will work independently of phenylalanine hydroxylase (PAH), correcting such forms of hyperphenylalaninemias regardless of the PAH mutations carried by the patient.     

42例苯丙酮尿症患儿早期诊断治疗与智能发育

目的 了解新生儿疾病筛查确诊、治疗的苯丙酮尿症（PKU）患儿的智能发育情况及与临床治疗的依从性关系. 方法 对1999～2009年经新生儿疾病筛查确诊为苯丙酮尿症的45例中的42例患儿分析其治疗情况,并选用Gesell发育量表对患儿的智能发育水平进行评估. 结果 45例PKU患儿2例放弃治疗、1例死亡、42例接受治疗;起始治疗年龄为25～269 d;生后40 d内起始治疗的患儿11例,无智能低下发生;起始治疗时间越早,患儿智能偏低和异常的比例越低,差异有统计学意义（P〈0.01）;家长态度完全配合治疗的占73.8%（31/42）,不配合治疗的占26.2%（11/42）;完全配合治疗组患儿除适应性和语言发育低于正常儿童组得分,差异有统计学意义（P〈0.05）外,大运动、精细运动和个人-社交发育与正常儿童组比较,差异均无统计学意义;不配合组患儿智能发育明显落后,5项观察项目与完全配合治疗组及正常组比较,差异均有统计学意义（P〈0.01）. 结论 新生儿疾病筛查是早期发现PKU患儿的有效方法;患儿起始治疗时间的早晚及家长配合治疗程度直接影响患儿治疗效果;若患儿能在生后1个月内治疗,同时家长给予配合,可以避免患儿智能水平低下的发生.