Novel therapeutic approaches to treatment of botulinum neurotoxin poisoning

治疗肉毒杆菌神经毒素中毒的新方法

基本信息

批准号：
10522051
负责人：
Konstantin Ichtchenko
金额：
$ 103.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522051
关键词：
Affect Affinity Animal Testing Antibody Therapy Antidotes Binding Bontoxilysin Botulism Budgets California Cavia Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chimeric Proteins Clinical Collaborations Communicable Diseases Cytoplasm Cytosol Data Development Disease Disease Outbreaks Event Exposure to FDA approved Goals Human Immunoglobulin Therapy In Vitro Induction of neuromuscular blockade Institutes Intoxication Light Metalloproteases Methods Molecular Motor Neurons Mus Nerve Neurodegenerative Disorders Neurons New York Paralysed Pathogenicity Pathway interactions Patients Pattern Peptide Hydrolases Pharmacological Treatment Physiological Poison Poisoning Production Property Prophylactic treatment Proteins Recording of previous events Recovery Regenerative Medicine Research Personnel Respiratory Paralysis Role SNAP receptor Scientist Serotyping Specificity Speed Supportive care Symptoms System Systems Development Targeted Toxins Testing Therapeutic Therapeutic Index Toxic effect Toxicology Treatment Efficacy United States Universities Veterinary Medicine Veterinary Schools acute toxicity antitoxin base botulinum botulinum toxin type B botulinum toxin type E cytotoxic delivery vehicle experience forest improved in vivo in vivo Model innovation lead candidate medical schools mutant nanobodies neuromuscular transmission neurotransmitter release next generation nonhuman primate novel novel therapeutic intervention pre-clinical presynaptic prevent public health priorities receptor respiratory side effect small molecule inhibitor small molecule therapeutics success symptom treatment targeted delivery therapeutic development therapeutic protein therapeutic target therapeutically effective trafficking treatment strategy ubiquitin ligase ventilation

项目摘要

PROJECT SUMMARY/ABSTRACT: Botulinum neurotoxin (BoNT) is a highly potent, neuroparalytic poison that cleaves presynaptic SNARE proteins required for neurotransmitter release. The primary toxic effect of BoNT poisoning is blockade of neuromuscular transmission, leading to flaccid paralysis and death by respiratory arrest. There are no specific countermeasures capable of reversing symptomatic botulism. Current treatment strategies for lethal exposures are limited to post-exposure prophylaxis via passive immunoglobulin therapy, which cannot prevent respiratory collapse once botulism symptoms emerge, and supportive care. In the event of a large-scale botulism outbreak or deliberate attack, there is limited ability to maintain large numbers of symptomatic victims on artificial ventilation for weeks or longer. Consequently, development of effective therapeutics for respiratory paralysis is a high priority for public health and national defense. A major limitation in creating an effective therapeutic for botulinum poisoning has been the inability to identify post-exposure treatments that block or terminate the molecular toxicity of the BoNT light chain (LC) within the nerve terminal. This project aims to develop a new class of botulism antidotes that exploit the natural neuronal receptors and trafficking pathways normally employed by the targeted toxin itself. Unlike available antibody-based therapeutics and small molecule inhibitors of the light chain metalloprotease, the botulinum neurotoxin (BoNT)‐based therapeutics that we have developed can reach an intracellular target in a post‐exposure setting. Unlike conventional small molecule therapeutics, which would equally affect all cells in the body with potentially deleterious side effects, the proposed method will specifically deliver a therapeutic moiety only to the cytosol of the target cells (neurons). This is a unique approach toward treating not only botulism, as embodied in this proposal, but also infectious and neurodegenerative diseases in which the causative agents reside and exert their action intra-neuronally. The team of scientists assembled for this project includes researchers with unique expertise who are well-qualified for the task at hand, including a long and successful history in generating BoNT-neutralizing nanobodies, extensive expertise in expressing neuron-targeted physiologically active fusion proteins that use metalloprotease-inactivated BoNT/C1 as a molecular vehicle for delivery of nanobodies, expertise in test systems for development of compounds promoting accelerated degradation of intracellular targets through the endogenous proteasomal system, and extensive experience in developing in vitro and in vivo models that can be used to test novel botulism antidotes.

项目摘要/摘要：肉毒神经毒素（BONT）是一种高潜力的神经分析毒物神经递质释放所需的蛋白质。骨中毒的主要毒性作用是封锁神经肌肉传播，导致呼吸停滞的瘫痪和死亡。没有具体的能够逆转有症状的肉毒杆菌的对策。当前致命暴露策略仅限于通过被动免疫球蛋白疗法预防暴露后预防，这无法阻止呼吸一旦出现肉毒杆菌症状崩溃，并提供了支持护理。如果发生大规模肉毒杆菌暴发或故意攻击，在人造上保持大量症状的能力有限通风几周或更长时间。因此，开发有效的呼吸麻痹疗法是公共卫生和国防的高度优先事项。为创建有效疗法的主要局限肉毒杆菌中毒一直是无法识别暴露后治疗的，以阻止或终止神经末端内骨轻链（LC）的分子毒性。该项目旨在开发一个新课程利用自然神经元接收器和贩运途径通常采用的肉毒杆菌抗原目标毒素本身。与可用的基于抗体的疗法和光的小分子抑制剂不同链金属蛋白酶，我们已经开发的基于肉毒杆菌神经毒素（BONT）的疗法可以达到暴露后环境中的细胞内目标。与常规的小分子疗法不同，这将同样会影响体内所有细胞具有潜在有害的副作用，该方法将专门仅向靶细胞（神经元）的胞质溶胶提供治疗部分。这是一种独特的方法不仅将肉毒杆菌视为本提案中体现的肉毒杆菌，还可以在病因代理人居住并在神经内发挥作用。科学家团队集会了该项目包括具有独特专业知识的研究人员，他们合格地完成了手头的任务，包括长期成功的历史，在产生散发纳米生物形成，表达广泛的专业知识方面使用金属蛋白酶灭活的BONT/C1的神经靶向物理活性融合蛋白作为A 用于递送纳米型的分子媒介物，用于开发化合物的测试系统专业知识通过内源性蛋白酶体系统加速细胞内靶标的降解，并广泛具有可用于测试新型肉毒杆菌疾病的体外和体内模型的经验。