[The safety and efficacy of adeno-associated virus-mediated LDLR transfection in homozygous familial hypercholesterolemia].

<b>Objective:</b> To evaluate the safety and efficacy of an adeno-associated virus vector carrying an optimized human low density lipoprotein receptor (LDLR) gene (NGGT006) in the treatment of homozygous familial hypercholesterolemia (HoFH) with LDLR mutations. <b>Methods:</b> This is an open-label, single-center, single-arm, non-randomized, investigator-initiated clinical trial. According to the dose-escalation principle, enrolled HoFH patients received a single injection of NGGT006 at three different doses: low dose (7.5×10¹² vg/kg), medium dose (1.5×10¹³ vg/kg), or high dose (3.0×10¹³ vg/kg). The primary endpoint of this study was the safety of NGGT006 treatment, evaluated by the incidence of drug-related adverse events and serious adverse events, and the efficacy of NGGT006 treatment, assessed by percentage and absolute changes in low density lipoprotein-cholesterol (LDL-C) levels. The early results of the first 3 patients after NGGT006 therapy in a 64-week follow-up were reported. <b>Results:</b> The 3 patients were aged 29 to 33 years, including 2 males, and the baseline serum LDL-C levels ranged from 8.95 to 11.17 mmol/L. No effective reduction in LDL-C levels was observed in patients 1 and 2, who were treated with low dose and medium dose of NGGT006, respectively. Patient 3 treated with a high dose of NGGT006 showed a rapid and persistent decrease in LDL-C levels. At the 64-week follow-up, the LDL-C level reduced from 11.17 mmol/L to 0.28 mmol/L, with a relative change of 97.49% compared with baseline. During the entire follow-up period, there were no serious adverse events in any of the patients. Only adverse events graded 2 or lower occurred, such as liver enzyme elevation and mild fever. <b>Conclusions:</b> NGGT006 gene therapy is generally safe and well-tolerated in HoFH patients with LDLR mutations. High-dose NGGT006 treatment can significantly reduce LDL-C levels. Further research is needed to evaluate its long-term efficacy.