Targeted-delivery of small interference RNA against anthrax

针对炭疽病的小干扰 RNA 的靶向递送

• 批准号: 9089923
• 负责人: MINGTAO ZENG
• 金额: $ 22.95万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089923
• 关键词: A/J Mouse; Aluminum Hydroxide; Amino Acids; Animals; Anthrax Vaccines; Anthrax disease; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigens; Antimicrobial Resistance; Arginine; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bacterial Infections; Binding; Bioterrorism; Biothrax; Blood Circulation; Blood capillaries; Cardiac Myocytes; Cell Survival; Cells; Cessation of life; Charge; Chimeric Proteins; Cleaved cell; Communicable Diseases; Complement; Complex; Containment; Cytosol; Development; Disease; Edema; Endocytosis; Exposure to; Formulation; Future; Gram-Positive Bacteria; Health; Hepatocyte; Human; Immune; Immune system; Immunity; Immunization; Immunization Schedule; Infection; Influenza; Kinetics; Label; Licensing; Lung; Mass Immunization; Modeling; Morphogenesis; Mus; Names; Patients; Peptides; Property; Prophylactic treatment; Proteins; Public Health; RNA Binding; RNA Interference; Receptor Cell; Reporter; Reporting; Reproduction spores; Research; Safety; Shock; Small Interfering RNA; Smooth Muscle; System; Technology; Therapeutic; Toxic effect; Toxin; Travel; Vaccination; Vaccines; Virulence; Virulence Factors; animal tissue; anthrax lethal factor; anthrax toxin; anthrax toxin receptors; antigen binding; biothreat; capillary; combat; cytotoxicity; design; edema factor; immunogenicity; improved; lymph nodes; macrophage; mouse model; novel; pathogen; prevent; prophylactic; protective efficacy; reaction rate; receptor binding; respiratory; success; targeted delivery; targeted treatment; tumor endothelial marker 8; vaccine candidate; weapons

 DESCRIPTION: Targeted-delivery of small interference RNA against anthrax. Anthrax is a serious disease caused by Bacillus afgfnthracis, a bacterium that forms spores. Anthrax most commonly occurs in wild and domestic mammalian species; but can also occur in humans when they are exposed to infected animals or animal tissues, or when anthrax spores are dispersed as a bioterrorist weapon. The complicated immunization schedule with the licensed vaccine BioThrax calls for a new and easily administered anthrax vaccine. Since anthrax is a disease that rarely occurs naturally in humans, it is more realistic to develop a post exposure prophylaxis or therapy instead of mass immunization, as with the current vaccine. Following exposure, macrophages ingest anthrax spores and travel to the lymph node where these spores germinate. The B. anthracis bacteria are then released into the bloodstream and produce toxins that are key factors in the virulence of disease: protective antigen (PA), edema factor (EF), and lethal factor (LF). PA is the receptor binding toxin component that attaches to either of two host cell receptors: anthrax toxin receptor 1 (ANTXR1 or tumor endothelial marker 8/TEM8) and anthrax toxin receptor 2 (ANTXR2 or capillary morphogenesis protein 2/CMG2). After binding, PA is cleaved and the receptor-bound portions form a heptameric pore that binds EF or LF. The toxin complexes are endocytosed and delivered into the cytosol. The activities of LeTx and EdTx result in malfunction of the immune system, edema, shock, and death. Our preliminary study has shown that inhibition of ANTXR expression by RNA interference (RNAi) technology using specific anti-ANTXR small interference RNA (siRNA) could prevent cytotoxicity of anthrax toxins. We hypothesize that a detoxified anthrax toxin could be used as a delivery vehicle for anti-ANTXR siRNA. In order to evaluate this hypothesis, we propose the following three specific aims: Specific Aim 1: To generate detoxified anthrax toxins for ANTXR-targeted siRNA delivery. Specific Aim 2: To assess the inhibitory effect on anthrax toxin induced cytotoxicity in ANTXR-silenced cells. Specific Aim 3: To evaluate efficacy of the anti-ANTXR siRNA treatment in a mouse model of anthrax. We anticipate that the proposed host-targeted treatment strategy will prevent severe illness and death in patients exposed to both wild type and even antibiotic-resistant B. anthracis spores by natural infection or a bioterrorist attack. Furthermore, this technology can be developed as a platform to treat other antimicrobial-resistant pathogens that employ pore-forming toxins as virulence factors.