Novel Intracellular Therapeutic Agent for Botulinum Intoxication

新型肉毒杆菌中毒细胞内治疗剂

• 批准号: 7611019
• 负责人: ANTHONY A Ferrante
• 金额: $ 24.36万
• 依托单位: PHYSICAL SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611019
• 关键词: Address; Adverse effects; Alzheimer' s Disease; Animal Model; Binding; Biological Assay; Bontoxilysin; Breathing; Carrier Proteins; Cells; Chimeric Proteins; Cholinergic Agents; Clinical; Clinical Trials; Clostridium; Cytoplasm; Development; Diphtheria Toxin; Disease; Dissociation; Dose; Exhibits; Family; General Population; Generations; Human; In Vitro; Individual; Ingestion; Inhibitory Concentration 50; Intoxication; Lethal Dose 50; Life; Methods; Nervous system structure; Neurons; Neurotoxins; Neurotransmitters; Nucleic Acids; Oligonucleotides; Paralysed; Parkinson Disease; Passive Immunization; Peripheral; Phase; Phase I Clinical Trials; Protein Binding Domain; Proteins; Proteolysis; Public Health; Range; Recombinant Vaccines; Recovery; Research; Respiratory Failure; Ricin; Route; Serotyping; Shiga Toxin; Source; Specificity; Survival Rate; Symptoms; Synaptic Membranes; System; Testing; Tetanus Toxin; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Toxic effect; Toxin; Toxin Conjugates; Vaccination; Vaccines; Vesicle; aptamer; base; biodefense; botulinum; cholinergic; improved; in vivo; inhibitor/antagonist; milligram; neurotransmitter release; novel; novel therapeutics; physical science; prevent; small molecule; tetanospasmin

DESCRIPTION (provided by applicant): Biodefense toxins such as ricin, botulinum neurotoxins, and Shiga toxin are a source of concern for terrorist attacks due to their high toxicity and the limited post-exposure treatment alternatives. Each of these protein toxins exhibits an enzymatic activity that is the basis of its toxicity. Inhalation and ingestion are the primary routes of entry for protein toxins, and once these molecules have entered the cell, treatment options are severely limited. Physical Sciences Inc. (PSI) proposes to develop highly specific binding agents that will inhibit the catalytic activity of botulinum neurotoxins (BoNT). The proposed novel therapeutics will incorporate materials and methods for efficient delivery of the agents to the cytoplasm of target cells thus reversing inhibition of neurotransmitter release. Phase I research will develop novel BoNT inhibitors and demonstrate their efficacy using both in vitro and cell-based assays. In Phase II the agents and delivery vehicles will be optimized and will be tested for their ability to prevent or reverse the effects of BoNT intoxication in live animal models. We anticipate that the proposed system will deliver sufficient quantities of therapeutic to the cytoplasm to increase the LD50 of the agents at least 10-fold and significantly reduce recovery time for BoNT exposure. PUBLIC HEALTH RELEVANCE: Post-exposure treatment options for protein toxins such as ricin and botulinum are limited. This research seeks to develop post-exposure therapies for protein toxin exposure that will greatly improve survival rates.

描述（由申请方提供）：生物防御毒素，如蓖麻毒素、肉毒杆菌神经毒素和滋贺毒素，由于其高毒性和有限的暴露后治疗替代方案，是恐怖袭击的一个关注来源。这些蛋白质毒素中的每一种都表现出作为其毒性基础的酶活性。吸入和摄入是蛋白质毒素进入的主要途径，一旦这些分子进入细胞，治疗方案就受到严重限制。物理科学公司(PSI)提出开发将抑制肉毒杆菌神经毒素（BoNT）的催化活性的高度特异性结合剂。所提出的新型治疗剂将结合用于将药剂有效递送至靶细胞的细胞质从而逆转神经递质释放的抑制的材料和方法。I期研究将开发新型BoNT抑制剂，并使用体外和基于细胞的测定来证明其功效。在第二阶段，将优化药剂和运载工具，并测试它们在活体动物模型中预防或逆转BoNT中毒效应的能力。我们预计，所提出的系统将向细胞质递送足够量的治疗剂，以使药剂的LD 50增加至少10倍，并显著减少BoNT暴露的恢复时间。公共卫生相关性：暴露后的治疗选择，如蓖麻毒素和肉毒杆菌蛋白毒素是有限的。这项研究旨在为蛋白质毒素暴露开发暴露后疗法，这将大大提高生存率。