To Evaluate the Safety and Efficacy of GS1168 Injection in Adult Phenylketonuria

A Clinical Exploration Study of Adeno-Associated Virus Vector Expressing Human Phenylalanine Hydroxylase Gene in Adult Classical Phenylketonuria

This study is a single-arm, open-label, dose-escalation, exploratory study to evaluate the safety, tolerability, and efficacy of a single administration of GS1168 Injection in Chinese adult phenylketonuria (PKU) with PAH mutation.

Inclusion Criteria:

1. Understand the purpose and risks of the study and voluntarily sign Informed Consent Forms (ICF).
2. Male or female, aged 18-55 years.
3. Diagnosis of PKU due to PAH mutation, and be inadequately controlled with current therapy (e.g., dietary management) in the judgement of the investigator.
4. Intolerant of unresponsive to available treatment such as Kuvan or Palynziq, and have come off the medication for at least 28 days prior to signing the ICF.
5. Ability and willingness to maintain dietary protein intake consistent with baseline
6. Male and female subjects of childbearing potential must agree to use effective contraception methods from signing ICF until at least 52 weeks after GS1168 infusion. Female subjects must not be breastfeeding.
7. Agree to avoid alcohol consumption from 30 days prior to GS1168 infusion until at least 52 weeks after infusion.
8. Ability to communicate well with the Investigator and to understand and comply with the requirements of the study.

Exclusion Criteria:

1. Diagnosis of PKU due to other gene mutations.

2. Body weight ≥100 kg or Body Mass Index (BMI) ≥30 kg/m² at screening.

3. Presence of anti-AAV8 neutralizing antibody.

4. Abnormal liver function tests at screening:

   • ALT or AST >1.25 × Upper Limit of Normal (ULN)
   • GGT >1.25 × ULN
   • Total Bilirubin >1.5 × ULN

5. Abnormal laboratory findings at screening:

   • Hemoglobin <9 g/dL
   • Neutrophil count <1.0 × 10⁹/L
   • Platelet count <100 × 10⁹/L
   • Serum Creatinine ≥1.5 mg/dL (133 μmol/L)
   • Glycated Hemoglobin (HbA1c) >6% or Fasting Blood Glucose >6.1 mmol/L

6. Active or occult hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection, positive Human Immunodeficiency Virus (HIV) antibodies and positive syphilis test.

7. Any severe conditions of respiratory, cardiovascular, gastrointestinal, renal, neurological, endocrine, immunological, hematological, psychiatric, etc.

8. History of malignancy.

9. Any other condition that, in the opinion of the Investigator, may affect subject compliance or render the subject unsuitable for participation in this trial.