nggt006 gene therapy for homozygous familial hypercholesterolemia

Conditions: Homozygous Familial Hypercholesterolemia

Summary: 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).

homozygous familial hypercholesterolemia (hofh) is a rare inherited disorder of lipoprotein metabolism, characterized by extreme elevations in low-density lipoprotein cholesterol (ldl-c) and leading to early onset of severe coronary artery disease. this is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of a single intravenous infusion of nggt006 in 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). 4-15 subjects will be enrolled and divided into 4 groups according to the principle of dose escalation, respectively administered intravenous infusion of nggt006 at dose group 1 (7.5e12vg/kg), dose group 2 (1.5e13vg/kg) , dose group 3 (3e13vg/kg) and dose group 4 (4e13vg/kg). the researcher is allowed to extend 0-3 patients. all subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.

Eligibility criteria:
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; * aav8 neutralizing antibodies can be negative or reduced to negative levels through methods such as plasma exchange. * untreated ldl-c ≥10 mmol/l (386mg/ dl) or treated ldl-c ≥7 mmol/l (270mg/ 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.

Keywords: homozygous familial hypercholesterolemia gene therapy low-density lipoprotein cholesterol