Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase

• Main Authors: Rui Tao, Lin Xiao, Lifang Zhou, Zhaoyue Zheng, Jie Long, Lixing Zhou, Minghai Tang, Biao Dong, Shaohua Yao
• Format: Article
• Language: English
• Published: Elsevier 2020-12-01
• Series: Molecular Therapy: Methods & Clinical Development
• Subjects: phenylketonuria; adeno-associated virus; phenylalanine amino lyase; gene therapy
• Online Access: http://www.sciencedirect.com/science/article/pii/S232905012030005X

Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutation within phenylalanine hydroxylase (PAH) gene. Loss-of-function of PAH leads to accumulation of phenylalanine in the blood/body of an untreated patient, which damages the developing brain, causing severe mental retardation. Current gene therapy strategies based on adeno-associated vector (AAV) delivery of PAH gene were effective in male animals but had little long-term effects on blood hyperphenylalaninemia in females. Here, we designed a gene therapy strategy using AAV to deliver a human codon-optimized phenylalanine amino lyase in a liver-specific manner. It was shown that PAL was active in lysing phenylalanine when it was expressed in mammalian cells. We produced a recombinant adeno-associated vector serotype 8 (AAV8) viral vector expressing the humanized PAL under the control of human antitrypsin (hAAT) promoter (AAV8-PAL). A single intravenous administration of AAV8-PAL caused long-term correction of hyperphenylalaninemia in both male and female PKU mice (strain Pahenu2). Besides, no obvious liver injury was observed throughout the treatment process. Thus, our results established that AAV-mediated liver delivery of PAL gene is a promising strategy in the treatment of PKU.