Samumed, LLC, San Diego, CA, USA.
Samumed, LLC, San Diego, CA, USA.
Spine J. 2020 Sep;20(9):1492-1502. doi: 10.1016/j.spinee.2020.04.024. Epub 2020 May 12.
Abnormal Wnt signaling in intervertebral discs (IVDs) progresses degenerative disc disease (DDD) pathogenesis by impairing nucleus pulposus cell function, decreasing matrix deposition, and accelerating fibrosis.
This study was conducted to evaluate the effects of lorecivivint (LOR; SM04690), a small-molecule Wnt pathway inhibitor, on IVD cells and in an animal model of DDD.
We used in vitro assays and a rat model of DDD to test the effects of LOR on nucleus pulposus cell senescence and viability, annulus fibrosus (AF) cell fibrosis, and cartilage regeneration and protection.
Wnt pathway gene expression was measured in human NP and AF cell cultures treated with LOR or DMSO (vehicle). Chondrocyte-like differentiation of rat and human NP cells, NP cell senescence and protection, and AF cell fibrosis were assessed using gene expression and immunocytochemistry. Disc and plasma pharmacokinetics were analyzed following intradiscal LOR injection in rats. In vivo effects of LOR and vehicle on AF integrity, AF/NP junction, NP cellularity and matrix, and disc height were compared using histopathology and radiography in a rat coccygeal IVD needle-puncture model of DDD.
In NP and AF cell cultures, LOR-inhibited Wnt pathway gene expression compared with vehicle. In NP cells, LOR inhibited senescence, decreased catabolism, and induced differentiation into chondrocyte-like cells; in AF cells, LOR decreased catabolism and inhibited fibrosis. A single intradiscal LOR injection in rats resulted in therapeutic disc concentrations (~30 nM) for >180 days and minimal systemic exposure. DDD-model rats receiving LOR qualitatively demonstrated increased cartilage matrix and reduced AF lamellar disorganization and fragmentation with significantly (p<.05) improved histology scores and increased disc height compared with vehicle.
LOR showed beneficial effects on IVD cells in vitro and reduced disease progression in a rat model of DDD compared with vehicle, suggesting that LOR may have disease-modifying therapeutic potential.
The current therapeutic options for DDD are pain management and surgical intervention; there are no approved therapies that alter the progression of DDD. Our data support advancing LOR into clinical development as an injectable, small-molecule, potential disease-modifying treatment for DDD in humans.
椎间盘（IVD）中异常的 Wnt 信号通过损害髓核细胞功能、减少基质沉积和加速纤维化来推进退行性椎间盘疾病（DDD）的发病机制。
本研究旨在评估小分子 Wnt 通路抑制剂 lorecivivint（LOR；SM04690）对 IVD 细胞和 DDD 动物模型的影响。
我们使用体外分析和 DDD 大鼠模型来测试 LOR 对髓核细胞衰老和活力、纤维环（AF）细胞纤维化以及软骨再生和保护的影响。
用 LOR 或 DMSO（载体）处理人 NP 和 AF 细胞培养物，测量 Wnt 通路基因表达。使用基因表达和免疫细胞化学评估大鼠和人 NP 细胞的软骨样分化、NP 细胞衰老和保护以及 AF 细胞纤维化。分析大鼠椎间盘内注射 LOR 后的椎间盘和血浆药代动力学。在 DDD 的大鼠尾骨 IVD 针穿刺模型中，通过组织病理学和放射照相术比较 LOR 和载体对 AF 完整性、AF/NP 交界处、NP 细胞密度和基质以及椎间盘高度的体内影响。
在 NP 和 AF 细胞培养物中，与载体相比，LOR 抑制了 Wnt 通路基因表达。在 NP 细胞中，LOR 抑制衰老、减少分解代谢并诱导向软骨样细胞分化；在 AF 细胞中，LOR 减少分解代谢并抑制纤维化。单次大鼠椎间盘内注射 LOR 可产生长达 180 天的治疗性椎间盘浓度（~30 nM），且全身暴露最小。与载体相比，接受 LOR 的 DDD 模型大鼠在组织学评分和增加的椎间盘高度方面表现出定性改善，软骨基质增加，纤维环层状结构紊乱和碎片化减少。
与载体相比，LOR 对体外 IVD 细胞表现出有益作用，并减少了 DDD 大鼠模型中的疾病进展，表明 LOR 可能具有疾病修饰治疗潜力。
DDD 的当前治疗选择是疼痛管理和手术干预；没有批准的疗法可以改变 DDD 的进展。我们的数据支持将 LOR 推进为人类 DDD 的可注射、小分子、潜在的疾病修饰治疗的临床开发。
