Branaplam是一种剪接调节剂,先前正在开发中,用作1型脊髓性肌萎缩症和亨廷顿氏病的治疗剂。Branaplam在临床前研究中增加了运动神经元存活蛋白的水平,并且在早期临床研究中具有良好的耐受性;然而,在一项幼犬的临床前安全性研究中观察到周围神经毒性.这项研究的目的是确定狗的血清神经丝轻链(NfL)浓度是否可以作为布拉那普利诱导的周围神经毒性的监测生物标志物。一项为期30周的时程调查研究,在用载体对照(阴性对照)治疗的狗中进行,神经毒性吡哆醇(阳性对照),或者进行Branaplam评估神经病理学,神经形态测量,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,在周围神经中观察到轻度至中度神经纤维变性,与血清NfL浓度增加有关,但是没有观察到电生理参数的迹象或变化。患有吡哆醇诱导的外周轴突变性的狗除了血清NfL升高外,还表现出临床体征和电生理变化。这项研究表明,NfL可能作为一种探索性生物标志物,有助于检测和监测治疗相关的周围神经损伤。有或没有临床症状,与服用branaplam和其他具有神经毒性风险的化合物有关。
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.