Safety and Efficacy Study of NGGT002 in PKU Adult Subjects

This study is designed to evaluate the safety and efficacy of NGGT002 gene therapy in adult subjects diagnosis with PKU due to confirmed PAH gene mutations indicative of PAH deficiency. NGGT002 will be administered via intravenous infusion. The study will begin with Dose Level 1, followed by a stepwise dose escalation. After evaluating the safety and efficacy data, a decision will be made to either expand the current cohort or proceed to the next dose level. The same process will be followed for subsequent dose cohorts.

Inclusion criteria

• Voluntarily sign informed consent form;
• Male and female subjects with diagnosis of PKU caused by confirmed phenylalanine hydroxylase(PAH) mutation according to the "Clinical Practice Guidelines for Phenylketonuria, 2020 Edition";
• Age ≥ 18 years;
• Blood phenylalanine (Phe) concentration ≥ 600 μmol/L at least once within 2 years prior to screening, with one measurement confirmed within six months of enrollment;
• Subjects are able to maintain their baseline diet throughout the study (regardless of dietary phenylalanine restriction), and willingness to follow the instruction of investigators to manage the diet for the duration of the trial;
• Subjects are required to obtain approval from the investigator prior to the use of any concomitant medications during the study period;
• Willingness and capable per Investigator opinion to comply with study procedures and requirements;
• Female participants of childbearing potential must have abstained from unprotected sexual intercourse for at least 14 days prior to dosing, and must have a documented negative serum hCG test between Day -7 and Day 0. All participants must be willing to use a highly effective method of contraception for at least 12 months following NGGT002.

Exclusion criteria

• Anti-AAV8 neutralizing antibody>1:10
• Prior gene therapy
• Positive hepatitis B virus surface antigen, hepatitis C virus antibody, anti-human immunodeficiency virus antibody or treponema pallidum-specific antibody
• Hepatic function abnormal: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × ULN; alkaline phosphatase (ALP) > 1.5 × ULN; total bilirubin (TBil) > 1.5 × ULN; international normalized ratio (INR) > 1.3
• Hematology values outside of the normal range (Hemoglobin < 110 g/L (male), < 100 g/L (female), white blood cells < 3.0 × 10^9/L, neutrophils < 1.5 × 10^9/L, platelet counts < 100 × 10^9/L;
• Hemoglobin A1c > 6%, or fasting glucose > 6.1 mmol/L;
• Clinically significant abnormalities in vital signs, physical examination findings, laboratory tests, or other assessments that, in the Investigator's judgment, are deemed unsuitable for study enrollment;
• Any contraindications to corticosteroid use or conditions potentially worsened by corticosteroids, as assessed by the Investigator, including but not limited to hypersensitivity to glucocorticoids, epilepsy, recent or unresolved bone fractures, ongoing wound healing, uncontrolled infections, or clinically significant osteoporosis;
• Subjects with a history of allergy to human serum albumin;
• All types of past and current malignancy;
• Severe diseases in the cardiovascular, respiratory, digestive tract, endocrine, kidney, blood, nervous, mental and other systems before screening;
• Subjects with history of live diseases, such as hepatitis, liver cirrhosis, liver cancer or other serious liver diseases;
• Subjects who participated in other clinical trails and took drugs within 3 months before screening;
• Other conditions that the Investigators deemed inappropriate for enrollment.