Development of Gene-Silencing Therapeutics for Pseudomonas aeruginosa

铜绿假单胞菌基因沉默疗法的开发

基本信息

批准号：
10451560
负责人：
David Elihu Greenberg
金额：
$ 112.55万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10451560
关键词：
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 Marketing Messenger RNA Methods Minimum Inhibitory Concentration measurement Modeling Morbidity - disease rate Multi-Drug Resistance Mus Mutation Nosocomial Infections Organism Pathogenicity Patients Penetration 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 Safety Sepsis Site Specificity Therapeutic Therapeutic Agents Tissues Toxic effect Toxicology Transcript Translational Repression Translations analytical method antimicrobial antimicrobial drug chronic infection combat comparison control 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 technology platform

项目摘要

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.

项目概要/摘要革兰氏阴性病原体对许多抗菌药物的耐药性越来越强。此外，管道对于新抗生素的需求很小，迫切需要新的疗法。这对患者来说尤其是个问题患有慢性感染或免疫功能低下的人。多重耐药铜绿假单胞菌已被疾病控制和预防中心认定为严重威胁。铜绿假单胞菌病因各种临床环境和宿主中的医疗保健相关感染，但在以下领域尤其具有破坏性：囊性纤维化（CF）患者。我们一直对使用称为 PPMO 的反义分子作为这些感染的潜在治疗方法。这些分子阻断信使 RNA 并阻止形成目标蛋白。我们已经证明 PPMO 可用于靶向对生命至关重要的基因需要生长的假单胞菌，例如 acpP、lpxC 或 rpsJ。我们证明阻断这些蛋白质对于假单胞菌在体外生长。我们还表明这些 PPMO 可以提高感染小鼠的存活率与假单胞菌。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 的特征假单胞菌分离株，对抗生素敏感且具有多重耐药性。此外，功效研究将在肺炎和血流感染模型中进行。此过程将产生 2-4 个 PPMO，将接受进一步的临床前测试，包括毒性、耐药性、药效学和药代动力学研究。到拟议项目结束时，牵头 PPMO 将接受所需的临床前测试向 FDA 提交 IND 申请。这种开发新型抗生素的创新方法，特别是针对 P. 铜绿假单胞菌，可以帮助扩大用于治疗的日益缩小的有效抗生素类别这些严重的、危及生命的感染。