Phenylketonuria is an inborn error of metabolism caused by loss of function of the liver-expressed enzyme phenylalanine hydroxylase and is characterized by elevated systemic phenylalanine levels that are neurotoxic. Current therapies do not address the underlying genetic disease or restore the natural metabolic pathway resulting in the conversion of phenylalanine to tyrosine. A family of hepatotropic clade F adeno-associated viruses (AAVs) was isolated from human CD34⁺ hematopoietic stem cells (HSCs) and one (AAVHSC15) was utilized to deliver a vector to correct the phenylketonuria phenotype in Pah^enu2 mice. The AAVHSC15 vector containing a codon-optimized form of the human phenylalanine hydroxylase cDNA was administered as a single intravenous dose to Pah^enu2 mice maintained on a phenylalanine-containing normal chow diet. Optimization of the transgene resulted in a vector that produced a sustained reduction in serum phenylalanine and normalized tyrosine levels for the lifespan of Pah^enu2 mice. Brain levels of phenylalanine and the downstream serotonin metabolite 5-hydroxyindoleacetic acid were restored. In addition, the coat color of treated mice darkened following treatment, indicating restoration of the phenylalanine metabolic pathway. Taken together, these data support the potential of an AAVHSC15-based gene therapy as an investigational therapeutic for phenylketonuria patients.

苯丙酮尿症是由肝脏表达的酶苯丙氨酸羟化酶功能丧失引起的先天性代谢错误，其特征是全身性苯丙氨酸水平升高，具有神经毒性。当前的疗法不能解决潜在的遗传疾病或恢复导致苯丙氨酸向酪氨酸转化的天然代谢途径。从人类CD34 ⁺造血干细胞（HSC）中分离出了一个家族的肝进化枝F腺相关病毒（AAVs），并利用其中一个（AAVHSC15）递送了一种载体来纠正Pah ^enu2小鼠的苯丙酮尿​​症表型。将含有密码子优化形式的人苯丙氨酸羟化酶cDNA的AAVHSC15载体以单次静脉内剂量的方式给予Pah ^enu2小鼠维持含苯丙氨酸的正常饮食。转基因的优化产生了一种载体，该载体在Pah ^enu2小鼠的整个生命周期中均导致血清苯丙氨酸的持续降低和酪氨酸水平的正常化。脑中的苯丙氨酸和下游5-羟色胺代谢产物5-羟基吲哚乙酸水平得以恢复。此外，处理后的小鼠的毛色变暗，表明苯丙氨酸代谢途径得以恢复。综上所述，这些数据支持了基于AAVHSC15的基因疗法作为苯丙酮尿症患者的研究疗法的潜力。