AAV Gene Therapy Clinical Study in Adult Classic PKU (PHEdom)

Inclusion Criteria:

1. Is willing and able to provide written, signed informed consent after the nature ofthe study has been explained and prior to any research-related procedures; a legallyauthorized representative may provide written consent and assent may be requested.

2. Male and female subjects with diagnosis of classic PKU, a condition characterized bysevere PAH deficiency with confirmed PAH mutations predicted with no residual enzymeactivity. A list of PAH mutations for classic PKU based on in vitro PAH activity (Himmelreich et al., 2018) and the genotype-phenotype correlation (Garbade et al.,

2019. can be found in BIOPKU genotypes database (http://www.biopku.org/pah).

3. Adults aged 18-55 at the time of informed consent

4. Subjects intolerant or unresponsive to available medical therapies, such as Kuvan,Playnzip, etc.

5. Subjects who have been on medications, such as Kuvan, Palynziq, etc but have comeoff for medical reasons or the patient's decision at least 28 days prior to signingthe consent form (Subjects who have good disease control on these existing therapieswill not be included in this study).

6. At least two documented measurements of Phe ≥ 600 μmol/L in the preceding 24 monthswith one measurement obtained > 6 months prior to enrollment and one measurementobtained < 6 months prior to enrollment. All Phe levels should be drawn whilesubjects are on a Phe restricted diet and in the absence of acute illness.

7. Subject has the record of at least 3 months of stable Phe-restricted diet as theirbaseline diet, but with persistently elevated phenylalanine (Phe) levels despitedietary adherence and has willingness to follow the instruction of dietitians tomanage the diet for the duration of the trial.

8. Willingness and capable per Investigator opinion to comply with study procedures andrequirements.

9. Women of child bearing potential must be confirmed as negative non pregnant subjectsby blood pregnancy test from day -28 to day 0. Subjects must agree to use a highlyeffective form of contraception from the time of NGGT002 administration until aminimum of 1 year after NGGT002 administration, and for male subjects, a minimum of 3 consecutive semen samples are negative for AAV8 after administration of NGGT002.Highly effective birth control methods include:

• documented vasectomy or permanent sterilization

• condom

• combined (estrogen and progestogen-containing) hormonal contraception (oral,intravaginal or transdermal)

• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable)

• intrauterine device

• intrauterine hormone-releasing system

• sexual abstinence is acceptable only as true abstinence and when in line withthe preferred and usual lifestyle of the subject. Periodic abstinence (e.g.,calendar, ovulation, hypothermal, post-ovulation) is not acceptable as a formof abstinence.

Exclusion Criteria:

1. Subjects with PKU that is not due to PAH mutation

2. Presence of anti-AAV8 neutralizing antibodies

3. Prior to dosing, subjects exceed the limit of any of the following liver functionand hematology tests in two consecutive blood laboratory tests:

• Alanine aminotransferase (ALT) >1.5×ULN and/or aspartate aminotransferase (AST) >1.5×ULN

• Alkaline phosphatase (ALP) >1.5×ULN

• Total bilirubin (TBil) >1.5×ULN, direct bilirubin >1.5×ULN

• International normalized ratio (INR) > 1.5

• Blood creatinine (Scr) >1.5×ULN

• Hematology values outside of the normal range (Hemoglobin <110 g/L (male), <100g/L (female), white blood cell <3.0×10^9/L, neutrophil <1.5×10^9/L, platelet <100×10^9/L)

• Hemoglobin A1c >6% or fasting glucose >6.1 mmol/L

4. At the time of screening, abnormal vital signs (i.e. Temperature<36.3°C or >37.4°C;Blood pressure<100/60 mmHg or >130/80 mmHg; heart rate <60/min or>100/min;respiratory rate <12/min or >18/min; oxygen saturation<95%), physical examination,laboratory tests, or other related results that have clinical significance, and theresearchers believe they are unsuitable for enrollment.

5. Contraindications to corticosteroid use or possible deterioration of corticosteroiduse assessed and determined by the Investigator.

6. Active infection with hepatitis A virus (HAV ribonucleic acid [RNA] positive),active or occult hepatitis B virus infection (positive HBV-DNA or anti-HBc positivewith negative hBsAg, HBV surface antigen), active infection with hepatitis C virus (HCV RNA positive), infection with the human immunodeficiency virus (HIV) asmeasured by antibodies to HIV-1 and HIV-2, active or latent infection withtuberculosis (TB) measured by Quantiferon Gold, infection with syphilis by rapidplasma regainn (RPR) and/or serum syphilis antibody, treponema pallidum particleagglutination (TPPA).

7. Subjects with history of liver disease such as clinically significant steatosis,fibrosis, non-alcoholic steatohepatitis (NASH) and cirrhosis, biliary disease within 6 months of informed consent; except for Gilbert's syndrome.

8. All types of past and current malignancy

9. Imaging (liver ultrasound) proved the existence of Liver fibrosis, liver cirrhosisand other serious liver diseases

10. Severe diseases in the cardiovascular, respiratory, digestive tract, endocrine,kidney, blood, nervous, mental and other systems before screening.

11. History of allergy to Albumin (Human)

12. The subjects who have Substance Use Disorder (for example alcohol, heroin,amphetamine, etc)

13. The subjects who have received any gene therapy in the past, regardless of when itwas administered.

14. The subjects who have received any investigational treatment and took drugs within 3months before screening (or 5 half-lives, if longer)

15. Subjects with elevated circulating serum alpha-fetoprotein (AFP)

16. Other conditions that the Investigators deemed inappropriate for enrollment, such asPKU severe comorbidities and conditions (i.e. renal insufficiency or kidney failure,osteoporosis, anemia, acid reflux or gastro-esophageal ulcer, major depression,epilepsy, etc.), which may be deteriorated with the potential risks of NGGT002.

17. Subjects who are presently on available medications for the treatment of PKU, suchas Kuvan, Palynziq, etc.

18. Subjects who weight over 100 Kg

19. Subjects who consume too much natural protein (>2 g/Kg body weight/day) in theirdaily diet

20. Breastfeeding subjects will not be included in the study