Wannemacher Rouven, Jubran-Rudolf Lorna, Zdora Isabel, Leitzen Eva, Rohn Karl, Sippel Virginie, Paschen Christoph, Blattmann Peter, Baumgärtner Wolfgang, Gerhauser Ingo, Steiner Michel Alexander
Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17, 30559 Hannover, Germany.
Neurobiol Dis. 2025 Jun 15;210:106917. doi: 10.1016/j.nbd.2025.106917. Epub 2025 Apr 16.
Sinbaglustat is a brain-penetrating small molecule that inhibits the non-lysosomal glucocerebrosidase (GBA2) and, with lower potency, glucosylceramide synthase (GCS). Sinbaglustat has passed clinical phase I. Our preclinical study assessed its efficacy in a transgenic mouse model of G gangliosidosis, lacking a functional β-galactosidase enzyme (Glb1). Starting at 4 weeks of age, mice were either treated with a nominal dose of 10 or 300 mg/kg/day of sinbaglustat or remained untreated. Wild-type (WT) mice served as control. Body weight, clinical and neurological signs, and motor function was assessed until 17-18 weeks (4 months) and 30 weeks (7 months) of age when mice were euthanized for ex vivo assessments. In comparison to WT, Glb1 mice showed the expected accumulation of G gangliosidosis-related sphingolipids, neuropathology, and behavioral deficits. Both dosages of sinbaglustat left G and lyso G levels in the brain unaffected but delayed the onset of motor impairment and progression of clinical disease in Glb1 mice with the higher dose being more efficacious. Histologically and immunohistochemically, both treatment groups of Glb1 mice displayed reduced neuronal vacuolation. Only the higher dose of sinbaglustat decreased axonal damage and astrogliosis, which was also associated with a decrease of the axonal/neuronal damage marker plasma neurofilament light at 4 months (17-18 weeks). Both doses of sinbaglustat increased the GBA2 substrate glucosylceramide (GluCer) in the brain, while only the high dose reduced GluCer and other glycosphingolipids (GSLs) in the periphery indicating additional inhibition of GCS. We conclude that sinbaglustat had a therapeutic-like effect in the G gangliosidosis mouse model.
辛巴格司他是一种可穿透血脑屏障的小分子，它能抑制非溶酶体葡萄糖脑苷脂酶（GBA2），对葡萄糖神经酰胺合酶（GCS）的抑制作用较弱。辛巴格司他已通过临床I期试验。我们的临床前研究评估了其在缺乏功能性β-半乳糖苷酶（Glb1）的G神经节苷脂沉积症转基因小鼠模型中的疗效。从4周龄开始，小鼠分别接受名义剂量为10或300mg/kg/天的辛巴格司他治疗或不接受治疗。野生型（WT）小鼠作为对照。评估小鼠的体重、临床和神经学体征以及运动功能，直至17 - 18周（4个月）和30周（7个月）龄，此时对小鼠实施安乐死以进行离体评估。与WT小鼠相比，Glb1小鼠表现出G神经节苷脂沉积症相关鞘脂的预期蓄积、神经病理学改变和行为缺陷。两种剂量的辛巴格司他均未影响大脑中G和溶血G的水平，但延迟了Glb1小鼠运动障碍的发作和临床疾病的进展，较高剂量的效果更显著。在组织学和免疫组织化学方面，Glb1小鼠的两个治疗组均显示神经元空泡化减少。只有较高剂量的辛巴格司他减少了轴突损伤和星形胶质细胞增生，这也与4个月（17 - 18周）时轴突/神经元损伤标志物血浆神经丝轻链的减少有关。两种剂量的辛巴格司他均增加了大脑中GBA2底物葡萄糖神经酰胺（GluCer）的含量，而只有高剂量降低了外周组织中的GluCer和其他糖鞘脂（GSLs），表明对GCS有额外的抑制作用。我们得出结论，辛巴格司他在G神经节苷脂沉积症小鼠模型中具有类似治疗的效果。
