Department of Biotechnology, Israel Institute for Biological Research, Ness Ziona 7410001, Israel.
Toxins (Basel). 2021 Sep 24;13(10):679. doi: 10.3390/toxins13100679.
Antitoxin, the only licensed drug therapy for botulism, neutralizes circulating botulinum neurotoxin (BoNT). However, antitoxin is no longer effective when a critical amount of BoNT has already entered its target nerve cells. The outcome is a chronic phase of botulism that is characterized by prolonged paralysis. In this stage, blocking toxin activity within cells by next-generation intraneuronal anti-botulinum drugs (INABDs) may shorten the chronic phase of the disease and accelerate recovery. However, there is a lack of adequate animal models that simulate the chronic phase of botulism for evaluating the efficacy of INABDs. Herein, we report the development of a rabbit model for the chronic phase of botulism, induced by intoxication with a sublethal dose of BoNT. Spirometry monitoring enabled us to detect deviations from normal respiration and to quantitatively define the time to symptom onset and disease duration. A 0.85 rabbit intramuscular median lethal dose of BoNT/A elicited the most consistent and prolonged disease duration (mean = 11.8 days, relative standard deviation = 27.9%) that still enabled spontaneous recovery. Post-exposure treatment with antitoxin at various time points significantly shortened the disease duration, providing a proof of concept that the new model is adequate for evaluating novel therapeutics for botulism.
抗毒素是唯一获准用于肉毒中毒治疗的药物，可中和循环中的肉毒神经毒素（BoNT）。然而，当已经有大量 BoNT 进入其靶神经细胞时，抗毒素就不再有效。其结果是肉毒中毒进入慢性期，其特征是长时间瘫痪。在这个阶段，通过新一代的神经元内抗肉毒毒素药物（INABDs）阻断细胞内毒素的活性，可能会缩短疾病的慢性期并加速恢复。然而，缺乏模拟肉毒中毒慢性期的充分动物模型，无法评估 INABDs 的疗效。在此，我们报告了一种通过亚致死剂量 BoNT 中毒诱导的兔肉毒中毒慢性期模型的开发。呼吸监测使我们能够检测到正常呼吸的偏差，并定量定义症状发作时间和疾病持续时间。BoNT/A 的 0.85 兔肌内半数致死剂量诱发了最一致和最长的疾病持续时间（平均=11.8 天，相对标准偏差=27.9%），仍能实现自发恢复。在不同时间点暴露后使用抗毒素治疗显著缩短了疾病持续时间，为新模型可用于评估肉毒中毒的新疗法提供了概念验证。
