Clinical Exploration Trial of YOLT-101 in the Treatment of Familial Hypercholesterolemia (FH)
This study is a single arm, open, single dose escalation trial aimed at evaluating the safety and tolerability of YOLT-101 administration in patients with familial hypercholesterolemia; Determination of YOLT-101 OBD; Preliminary evaluation of the effects of single administration of YOLT-101 on plasma lipid and lipoprotein levels. Note: OBD is defined as the dosage at which plasma PCSK9 protein levels decrease between 60% and 95% from baseline on the 28th day after YOLT-101 administration. OBD ≤ Maximum Tolerable Dose (MTD). In this study, the longest screening period for the main study was 42 days, the treatment day was Day 1 (D1), and the safe follow-up period was up to 52 weeks after medication. In the main study, when OBD occurs, additional subjects will be added to the dose group (specific number of cases will be negotiated between the cooperating organization and investigators) for further validation. In addition, subjects in the first dose group can voluntarily receive a second drug administration of OBD level. After the completion of the main study, participants will undergo long-term follow-up. According to the Technical Guidelines for Long term Follow up Clinical Research of Gene Therapy Products (Trial) released by CDE, a long-term follow-up until 15 years after the medicine administration is required .
• Male or female, aged 18 to 75 years inclusive, at the time of signing informed consent.
• Meets the diagnostic criteria for familial hypercholesterolemia.
• At screening, there is a mutation in the PCSK9 and/or ApoB and/or LDLR gene.
• At screening, weight is ≥40kg, and Body Mass Index (BMI) is \>18kg/m\^2.
• At screening, subjects must meet the following laboratory criteria:
⁃ 1 Hematology: Absolute Neutrophil Count (ANC) ≥1.5×10\^9/L, Platelet (PLT) ≥100×10\^9/L, Hemoglobin (HGB) ≥90 g/dL; 5.2 Liver Function: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) \<2.0×Upper Limit of Normal (ULN), Total Bilirubin (TBIL) ≤1.5×ULN; 5.3 Renal Function: Serum Creatinine (Cr) ≤1.5×ULN, and Glomerular Filtration Rate (GFR) \>60mL/min\*1.73m\^2; 5.4 Coagulation Function: Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR) \<1.5×ULN; 5.5 Fasting Triglycerides \<5.6mmol/L.
• On moderate intensity or higher statin therapy (statin treatment stable for 4 weeks) with LDL-C ≥2.6mmol/L; for those with evidence of atherosclerosis, LDL-C ≥1.8mmol/L. (Evidence of atherosclerosis includes: 1. History of myocardial infarction, angina, coronary artery revascularization, non-embolic ischemic stroke or transient ischemic attack, intermittent claudication; 2. Presence of advanced subclinical atherosclerosis: Coronary artery calcium score \> 100 Agatston units, or above the 75th percentile for age and sex; or coronary artery CT angiography showing stenosis \> 50%, or multiple vessels with non-obstructive plaques.)
• Subjects and their partners must use effective contraceptive measures during the study period and for at least 6 months after the end of the main study.
• Voluntarily sign informed consent.