Inclusion Criteria: * Adults 18-55 years of age at the time of informed consent * Diagnosis of classical phenylketonuria (PKU) due to PAH deficiency * Four baseline plasma Phe values with a concentration of ≥ 600 μmol/L and at least one historical value ≥ 600 μmol/L in the preceding 24 months. * Participants must have uncontrolled classical PKU disease (despite Phe-restricted dietary management) in the judgment of the investigator and confirmed by the independent DMC at the end of the Screening period. * Participant has the ability and willingness to maintain their baseline diet, for the duration of the trial, unless otherwise directed Exclusion Criteria: * Subjects with PKU that is not due to PAH deficiency * Presence of anti-AAVHSC15 neutralizing antibodies * Participants who are well controlled on a Phe-restricted diet. * Hemoglobin A1c \>6.5% or fasting glucose \>126 mg/dL * Liver function tests \> ULN * International normalized ratio (INR) \> 1.2 * Hematology values outside of the normal range * Previously received gene therapy for the treatment of any condition.