Overview

This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of an intravenous infusion of NGGT006 in homozygous familial hypercholesterolemia (HoFH) patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C).

Eligibility

Inclusion Criteria:

• Voluntarily sign informed consent form;
• Male or female, 12 ≤ age ≤ 55 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene;
• Serum anti-AAV conjugate antibodies titer ≤ 1:80 and anti-AAV neutralizing antibodies titer ≤ 1:5;
• Untreated LDL-C >10 mmol/L (180mg/ dL) or treated LDL-C ≥7 mmol/L (126 mg/ dL) together with cutaneous or tendon xanthoma before age 18 years;
• Had been on stable medication for ≥30 days if receiving lipid-lowering therapy (or ≥60 days if receiving alirocumab or evolocumab) prior to screening and not scheduled for addition of new drugs or dose adjustments during the study;
• Agreed to follow a low-fat diet and comply with all study procedures;
• Agreed to maintain a similar exercise volume and intensity to baseline during the study period;
• Agreed to maintain good lifestyle habits;
• No history of alcohol abuse or alcohol dependence (diagnosed as F10 in ICD-10 code);
• No sexual activity for 14 days prior to administration and negative serum pregnancy test in female participants;
• Participants of childbearing potential agreed to use highly effective contraception for at least 365 days from administration of NGGT006;
• No plan of stent implantation within 3 months.

Exclusion Criteria:

• Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV) or syphilis test;
• Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) >2 × ULN;
• Baseline blood pressure >160/100 mmHg (1 repeat measurement is allowed);
• Uncontrolled myocardial infarction or heart failure, or had surgery plan within 1 year;
• Diabetes diagnosed within 3 months or with poor control (HbA1c >9%);
• Acute or chronic kidney failure;
• Hemoglobin (Hb) < 120g/L (male), Hb < 110 (female);
• Abnormal platelet counts or morphology;
• History or laboratory tests suggestive of thrombosis;
• Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer);
• Life expectancy less than 1 year;
• With malignant tumors;
• Liver fibrosis or liver cancer;
• Previous gene therapy treatment;
• Hypersensitivity to AAV or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus);
• Participation in any other clinical trial within 3 months;
• History of stent implantation within 1 month or myocardial infarction within 3 months;
• Breastfeeding females;
• Any other condition that may not be appropriate for the study in the opinion of the Investigator.