Diethilde Theil, Jens Kuhle, Dominique Brees, Elaine Tritto, François Pognan, Wilfried Frieauff, Kelley Penraat, Emily Meseck, Reginald Valdez, Andreas Hartmann
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引用次数: 2
Abstract
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.
期刊介绍:
Toxicologic Pathology is dedicated to the promotion of human, animal, and environmental health through the dissemination of knowledge, techniques, and guidelines to enhance the understanding and practice of toxicologic pathology. Toxicologic Pathology, the official journal of the Society of Toxicologic Pathology, will publish Original Research Articles, Symposium Articles, Review Articles, Meeting Reports, New Techniques, and Position Papers that are relevant to toxicologic pathology.