Development of Gene-Silencing Therapeutics for Pseudomonas aeruginosa

铜绿假单胞菌基因沉默疗法的开发

• 批准号: 10203746
• 负责人: David Elihu Greenberg
• 金额: $ 105.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10203746
• 关键词: Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antisense Oligonucleotides; Automobile Driving; Bacteremia; Bacterial Infections; Biological; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Collaborations; Collection; Cystic Fibrosis; Development; Dose; Drug Kinetics; Drug resistance; Duchenne muscular dystrophy; Effectiveness; Enzyme-Linked Immunosorbent Assay; Enzymes; Essential Genes; FDA approved; Formulation; Frequencies; Gene Silencing; Gene Targeting; Genes; Goals; Immunocompromised Host; In Vitro; Infection; Investigation; Lead; Libraries; Life; Lipid A; Lung; Lung infections; Messenger RNA; Methods; Minimum Inhibitory Concentration measurement; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutation; Nosocomial Infections; Organism; Pathogenicity; Patients; Peptide Library; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Pneumonia; Positioning Attribute; Preclinical Testing; Process; Production; Protein Subunits; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Regimen; Research; Resistance; Resistance development; Ribosomes; Risk; Rodent; Sepsis; Site; Specificity; Technology; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Toxicology; Transcript; Translations; analytical method; antimicrobial; antimicrobial drug; base; chronic infection; combat; cystic fibrosis patients; drug discovery; efficacy evaluation; efficacy study; fatty acid biosynthesis; healthcare-associated infections; improved; in vivo; indexing; innovation; interest; loss of function; mortality; multidrug-resistant Pseudomonas aeruginosa; novel; novel therapeutics; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; phosphorodiamidate morpholino oligomer; pneumonia model; pre-clinical; preclinical development; prevent; resistance frequency; resistant strain; safety study; screening; small molecule; success

PROJECT SUMMARY/ABSTRACT Gram-negative pathogens are becoming increasingly resistant to many antimicrobials. Furthermore, the pipeline for new antibiotics is small and new therapies are urgently needed. This can be especially problematic in patients who suffer from chronic infections or are immunocompromised. Multidrug-resistant Pseudomonas aeruginosa has been identified by the Centers for Disease Control and Prevention as a serious threat. P. aeruginosa causes healthcare associated infections in a variety of clinical settings and hosts, but is particularly devastating in patients with cystic fibrosis (CF). We have been interested in using antisense molecules called PPMOs as potential therapeutics in these infections. These molecules block messenger RNA and prevent the formation of the target protein. We have demonstrated that PPMOs can be used to target genes that are essential for Pseudomonas to grow, such as acpP, lpxC or rpsJ. We showed that blocking these proteins are essential for Pseudomonas to grow in vitro. We also showed that these PPMOs improve survival in mice that were infected with Pseudomonas. For this project, we propose to further characterize our lead PPMOs in a larger collection of Pseudomonas isolates, both antibiotic-sensitive and multidrug-resistant. In addition, efficacy studies will be performed in both models of pneumonia and bloodstream infection. This process will result in 2-4 PPMOs that will undergo further pre-clinical testing including toxicity, resistance, pharmacodynamic and pharmacokinetic studies. By the end of the proposed project, a lead PPMO will have undergone the needed pre-clinical testing for IND submission to the FDA. This innovative approach to developing novel antibiotics, particularly for P. aeruginosa, could help expand the increasingly shrinking classes of effective antibiotics that are used to treat these severe, life-threatening infections.

项目总结/摘要 革兰氏阴性病原体对许多抗菌剂的耐药性越来越强。此外，管道 新的抗生素是很小的，新的治疗方法是迫切需要的。这在患者中可能尤其成问题 患有慢性感染或免疫功能低下的人。多重耐药铜绿假单 已被疾病控制和预防中心确定为严重威胁。铜绿假单胞菌引起 在各种临床环境和宿主中的医疗保健相关感染，但在 囊性纤维化（CF）患者。我们一直对使用称为PPMO的反义分子感兴趣， 这些感染的潜在治疗方法。这些分子阻断信使RNA并阻止 目标蛋白质。我们已经证明，PPMOs可以用于靶向基因，这些基因对于 假单胞菌生长，如acpP，lpxC或rpsJ。我们发现，阻断这些蛋白质对于 假单胞菌在体外生长。我们还发现，这些PPMO提高了受感染小鼠的存活率， 假单胞菌对于这个项目，我们建议在更大的集合中进一步描述我们的主要PPMO， 假单胞菌分离株，包括对抗生素敏感和多重耐药。此外，疗效研究将 在肺炎和血流感染的两种模型中进行。这一过程将产生2-4个PPMO， 将进行进一步的临床前试验，包括毒性、耐药性、药效学和药代动力学 问题研究在拟议项目结束时，PPMO负责人将完成所需的临床前测试 向FDA提交IND申请。这种创新的方法开发新的抗生素，特别是对P。 铜绿假单胞菌，可以帮助扩大日益缩小的有效抗生素类别，用于治疗 这些严重的、危及生命的感染。