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/m².
Within at least 14 days (or 5 half-lives of the drug, whichever is longer, for small molecule/small nucleic acid drugs) or 2 months (for biological agents such as PCSK9 inhibitors) or 1 year (for PCSK9 small nucleic acid drugs) before accepting the study medication, those who have used prescription drugs that affect lipid metabolism other than statins, or those who have used any non-prescription drugs affecting lipid metabolism within at least 14 days before accepting the study medication (such as traditional Chinese medicine/patent Chinese medicine, vitamins, fish oil (>1000mg/day), drugs or health products containing red yeast rice, etc.; except for those who have been on stable non-cyclic hormone replacement therapy for more than 8 weeks and agree not to change the treatment plan for at least 28 days after receiving the trial medication); those who are currently participating in other clinical studies of lipid-lowering drugs and have used study medication.
Patients with poorly controlled hypertension (systolic blood pressure (SBP) ≥160mmHg and/or diastolic blood pressure (DBP) ≥100mmHg).
Patients with poorly controlled diabetes (glycated hemoglobin >8.5%).
Those allergic to drugs or components of LNP-mRNA vaccines contained in lipid nanoparticles (LNP), or those who have experienced adverse reactions due to LNP-based drug treatment, such as: 4.1 After receiving LNP-based drug treatment, ALT or AST > 3.0×ULN; 4.2 After receiving LNP-based drug treatment, INR > 1.5 or APTT/d-dimer > 1.5×ULN; 4.3 Any infusion reaction that requires clinical intervention or slows down or stops the infusion of LNP-based drug treatment; 4.4 Any other adverse reactions deemed related to LNP-based drug treatment by the investigator.