Neuronal delivery of antibodies has therapeutic effects in animal models of botulism.

Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets.

肉毒中毒是由一种强效的神经毒素引起的，这种毒素会阻断神经肌肉传递，导致窒息死亡。目前，治疗选择有限且没有解毒剂。在此，我们利用肉毒神经毒素（BoNT）的一种无毒衍生物的结构和运输特性，将一种功能阻断性单域抗体运输到神经元胞质中，在那里它可以抑制BoNT A型血清型（BoNT/A1）的分子毒性。症状出现后的治疗缓解了肉毒中毒的毒性症状，并在致命的BoNT/A1攻击后挽救了小鼠、豚鼠和非人灵长类动物。这些数据表明，无毒的BoNT衍生物可被用于将治疗性蛋白质部分递送到神经元细胞质中，在实验模型中它们在那里结合并中和细胞内靶点。这个平台的通用性可能使抗体和其他基于蛋白质的治疗药物能够递送到以前无法到达的神经内靶点。