Kim Ha-Yeon, Cho Jaeso, Park Min Kyu, Min Dal-Hee, Hwang Jun Gi, Won Cheolhee
Department of Clinical Pharmacology, ChungBuk National University College of Medicine, Cheongju, Republic of Korea.
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Clin Transl Sci. 2025 Apr;18(4):e70207. doi: 10.1111/cts.70207.
This study evaluated the safety, tolerability, and pharmacokinetics of LEM-S401, a novel siRNA therapeutic with DegradaBALL, a mesoporous silica nanoparticle-based delivery system. LEM-S401 is designed to deliver siRNA targeting connective tissue growth factor (CTGF) to fibroblasts for treating hypertrophic scars and keloids, both of which result from abnormal collagen proliferation. LEM-S401, containing unmodified siRNA LEM-17234 encapsulated in DegradaBALL nanoparticles, was administered subcutaneously to healthy adults in a randomized, double-blind, placebo-controlled, single-ascending dose study. Safety and tolerability assessments included vital signs, adverse events (AEs), laboratory tests, and cytokine levels. Pharmacokinetic analysis of LEM-17234 and silicon (Si), the primary component of DegradaBALL, was performed using blood samples collected at specified time points. LEM-S401 demonstrated a favorable safety and tolerability profile with only mild, self-resolving injection site reactions including pain and erythema. No systemic AEs were observed, and cytokine levels showed no significant changes between the treatment and placebo groups. Pharmacokinetic analysis revealed that LEM-17234 was below the plasma detection limit, indicating no notable systemic exposure of siRNA, while Si showed no dose-dependent systemic exposure, suggesting minimal systemic circulation of the mesoporous silica nanoparticles. These findings suggest DegradaBALL effectively encapsulates and delivers siRNA locally without significant systemic exposure. The novel DegradaBALL delivery system enables the stable and targeted delivery of siRNA, which presumably overcomes challenges related to siRNA instability and off-target effects. LEM-S401 has the potential to advance the treatment of fibrotic skin diseases such as keloids and hypertrophic scars by delivering siRNA directly to fibroblasts, thereby inhibiting excessive collagen production. Trial Registration: ClinicalTrials.gov identifier: NCT04707131. https://clinicaltrials.gov/study/NCT04707131?cond=NCT04707131&rank=1.
本研究评估了LEM-S401的安全性、耐受性和药代动力学。LEM-S401是一种新型的小干扰RNA（siRNA）疗法，采用基于介孔二氧化硅纳米颗粒的DegradaBALL递送系统。LEM-S401旨在将靶向结缔组织生长因子（CTGF）的siRNA递送至成纤维细胞，用于治疗肥厚性瘢痕和瘢痕疙瘩，这两种疾病均由胶原蛋白异常增殖引起。在一项随机、双盲、安慰剂对照、单剂量递增研究中，将含有包裹在DegradaBALL纳米颗粒中的未修饰siRNA LEM-17234 的LEM-S401皮下注射给健康成年人。安全性和耐受性评估包括生命体征、不良事件（AE）、实验室检查和细胞因子水平。使用在特定时间点采集的血样对LEM-17234和DegradaBALL的主要成分硅（Si）进行药代动力学分析。LEM-S401表现出良好的安全性和耐受性，仅出现轻微的、可自行缓解的注射部位反应，包括疼痛和红斑。未观察到全身性不良事件，治疗组和安慰剂组之间的细胞因子水平无显著变化。药代动力学分析显示，LEM-17234低于血浆检测限，表明siRNA无明显的全身暴露，而Si未显示出剂量依赖性的全身暴露，提示介孔二氧化硅纳米颗粒的全身循环极少。这些发现表明DegradaBALL能有效包裹并在局部递送siRNA，而无明显的全身暴露。新型DegradaBALL递送系统能够稳定且靶向递送siRNA，这可能克服了与siRNA不稳定性和脱靶效应相关的挑战。LEM-S401有潜力通过将siRNA直接递送至成纤维细胞，从而抑制过量胶原蛋白生成，推进瘢痕疙瘩和肥厚性瘢痕等纤维化皮肤病的治疗。试验注册：ClinicalTrials.gov标识符：NCT04707131。https://clinicaltrials.gov/study/NCT04707131?cond=NCT04707131&rank=1。
