Here, we have studied the in vivo potential of AONs used in different doses and routes of delivery as splicing-directed therapy for a liver enzyme, using as model targeted exon skipping in the phenylalanine hydroxylase (Pah) gene, resulting in an increase of phenylalanine (L-Phe) in body fluids (also termed hyperphenylalaninemia or HPA), as occurs in phenylketonuria (PKU, MIM#261600), a well-studied metabolic disease of autosomal recessive inheritance. The gene discussed is PAH; the disease is phenylketonuria.