Novartis Pharma AG, Basel, Switzerland.
F. Hoffmann-La Roche AG, Basel, Switzerland.
Toxicol Pathol. 2023 Apr;51(3):135-147. doi: 10.1177/01926233231180179. Epub 2023 Jul 12.
Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.
Branaplam 是一种剪接调节剂，此前正在开发用于治疗 1 型脊髓性肌萎缩症和亨廷顿病。Branaplam 增加了临床前研究中生存运动神经元蛋白的水平，并且在早期临床研究中耐受性良好；然而，在幼年犬的临床前安全性研究中观察到周围神经毒性。本研究旨在确定犬血清神经丝轻链（NfL）浓度是否可作为监测 branaplam 诱导的周围神经毒性的生物标志物。对接受 vehicle 对照（阴性对照）、神经毒性吡哆醇（阳性对照）或 branaplam 治疗的犬进行了 30 周时间过程研究，以评估神经病理学、神经形态计量学、电生理测量、基因表达谱以及与 NfL 血清浓度的相关性。在 branaplam 治疗的动物中，在外周神经中观察到轻度至中度神经纤维变性，与血清 NfL 浓度升高相关，但没有观察到电生理参数的迹象或变化。与 pyridoxine 诱导的周围轴突变性的犬除了血清 NfL 升高外，还表现出临床症状和电生理变化。这项研究表明，NfL 可能作为一种探索性生物标志物有用，以帮助检测和监测与 branaplam 和其他具有神经毒性风险的化合物给药相关的治疗相关的周围神经损伤，无论是否有临床症状。
