Gene silencing therapeutics for chronic infections in cystic fibrosis
囊性纤维化慢性感染的基因沉默疗法
基本信息
- 批准号:8511030
- 负责人:
- 金额:$ 24.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-03-01 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:Acyl Carrier ProteinAnabolismAnimalsAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsAntisense TechnologyBiological AssayBurkholderiaBurkholderia cepacia complexCell WallChemistryChronicClinicalCystic FibrosisDatabasesDeteriorationDevelopmentDiseaseDrug resistanceEscherichia coliEssential GenesFutureGene SilencingGene TargetingGenesGoalsGrowthHumanIn VitroInfectionLactamaseLeadLipopolysaccharidesLungMessenger RNAMethodsMicrobial BiofilmsMinimum Inhibitory Concentration measurementModelingMorbidity - disease rateMulti-Drug ResistanceMusPathway interactionsPatientsPeptidesPeptidoglycanPharmaceutical PreparationsPhasePhysiologicalPredispositionProteinsPseudomonasPseudomonas aeruginosaPublic HealthResearch DesignResistanceRespiratory physiologyRoleSalmonellaStructureSyndromeTestingTherapeuticTherapeutic AgentsWorkantimicrobialbacterial resistancecystic fibrosis patientsefflux pumpfatty acid biosynthesisfightingimprovedin vivointerestmortalitymouse modelnovelpathogenphosphorodiamidate morpholino oligomerpublic health relevanceresistance mechanismresponsetherapeutic developmenttherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Gram-negative pathogens are becoming increasingly resistant to currently used antimicrobials. Furthermore, the pipeline for new antibiotics is slim and new therapies are urgently needed. This can be especially problematic in patients who suffer from chronic infections. Examples of inherently drug resistant Gram-negative pathogens are Pseudomonas aeruginosa and the Burkholderia cepacia complex (Bcc). These pathogens cause disease in a variety of settings, but are particularly devastating in patients with cystic fibrosis (CF). Chronic P. aeruginosa or Bcc infection can lead to both progressive pulmonary decline, as well as in Bcc infection, rapid deterioration in lung function referred to as "cepacia syndrome." We have been interested in using antisense molecules called PPMOs as potential therapeutics in these infections. These molecules block messenger RNA and block the formation of protein. We have demonstrated that PPMOs can be used to target genes that are essential for these pathogens to grow, specifically the gene acpP (that encodes the protein acyl carrier protein). We showed that blocking this protein is essential for Burkholderia and Pseudomonas to grow in vitro. We also showed that this PPMO improves survival in mice that were infected with Burkholderia. For this project, we propose to find other essential gene targets in these pathogens that can be blocked with PPMOs, and perform studies to evaluate the most promising compounds ability to improve survival in mouse models of infection. In the first phase of the project, we will target pathways that have been shown in other Gram-negative pathogens to be essential for growth. These will include genes important in the development of the cell wall and associated structures (lipopolysaccharide and peptidoglycan biosynthesis) as well as fatty acid biosynthesis (i.e. acyl carrier protein). In addition, we will try to block the genes that pla a role in antibiotic resistance to see if we can restore activity of currently existing antibiotics. he second phase of the project will be to evaluate lead PPMO candidates in mouse models of infection. We will use the PPMOs as treatments in pulmonary models of infection, assessing both systemic and pulmonary delivery of the compound. By the conclusion of this study, we hope to have promising novel treatments for two of the most devastating pathogens in CF that could advance to further clinical development. This work has implications not only for these infections in CF, but for other medically important Gram-negative pathogens.
描述(由申请人提供):革兰氏阴性病原体越来越抗当前使用的抗菌药物。此外,新抗生素的管道很苗条,迫切需要新的疗法。对于患有慢性感染的患者,这尤其有问题。固有的耐药革兰氏阴性病原体的例子是铜绿假单胞菌和伯克霍尔德cepacia综合体(BCC)。这些病原体在各种情况下引起疾病,但在囊性纤维化(CF)患者中尤其是毁灭性的。慢性铜绿假单胞菌或BCC感染可导致肺的进行性下降,也可以导致BCC感染,肺功能快速恶化,称为“ Cepacia综合征”。我们对使用称为PPMO的反义分子作为这些感染的潜在疗法感兴趣。这些分子阻止了信使RNA并阻止蛋白质的形成。我们已经证明,PPMO可用于靶向这些病原体生长至关重要的基因,特别是基因ACPP(编码蛋白酰基载体蛋白)。我们表明,阻断该蛋白对于Burkholderia和Pseudomonas在体外生长至关重要。我们还表明,这种PPMO改善了被Burkholderia感染的小鼠的生存。对于该项目,我们建议在这些病原体中找到其他基因靶标,这些基因靶标可以用PPMO阻断,并进行研究以评估提高感染小鼠模型中生存的最有希望的化合物的能力。在项目的第一阶段中,我们将针对其他革兰氏阴性病原体显示的途径对生长至关重要。这些将包括对细胞壁和相关结构(脂多糖和肽聚糖生物合成)以及脂肪酸生物合成(即酰基载体蛋白)的重要基因。此外,我们将尝试阻止在抗生素耐药性中发挥作用的基因,以查看我们是否可以恢复当前现有抗生素的活性。该项目的第二阶段将是评估小鼠感染模型中的铅PPMO候选者。我们将使用PPMO作为感染肺模型的治疗方法,评估该化合物的全身和肺部递送。通过这项研究的结论,我们希望对CF中两种最具毁灭性病原体的新型治疗有希望,可以进一步发展临床发育。这项工作不仅对CF中的这些感染有影响,而且对其他重要的医学革兰氏阴性病原体有影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)
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David Elihu Greenberg其他文献
David Elihu Greenberg的其他文献
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{{ truncateString('David Elihu Greenberg', 18)}}的其他基金
Antibiotic Resistance Determination Utilizing Machine Learning
利用机器学习确定抗生素耐药性
- 批准号:
10442982 - 财政年份:2022
- 资助金额:
$ 24.83万 - 项目类别:
Antibiotic Resistance Determination Utilizing Machine Learning
利用机器学习确定抗生素耐药性
- 批准号:
10663905 - 财政年份:2022
- 资助金额:
$ 24.83万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 24.83万 - 项目类别:
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:
10451560 - 财政年份:2019
- 资助金额:
$ 24.83万 - 项目类别:
Gene silencing therapeutics for chronic infections in cystic fibrosis
囊性纤维化慢性感染的基因沉默疗法
- 批准号:
9248236 - 财政年份:2013
- 资助金额:
$ 24.83万 - 项目类别:
Gene silencing therapeutics for chronic infections in cystic fibrosis
囊性纤维化慢性感染的基因沉默疗法
- 批准号:
9039523 - 财政年份:2013
- 资助金额:
$ 24.83万 - 项目类别:
Novel gene-silencing therapeutics for multidrug-resistant gram-negative pathogens
针对多重耐药革兰氏阴性病原体的新型基因沉默疗法
- 批准号:
9055626 - 财政年份:2012
- 资助金额:
$ 24.83万 - 项目类别:
Novel gene-silencing therapeutics for multidrug-resistant gram-negative pathogens
针对多重耐药革兰氏阴性病原体的新型基因沉默疗法
- 批准号:
8842086 - 财政年份:2012
- 资助金额:
$ 24.83万 - 项目类别:
Novel gene-silencing therapeutics for multidrug-resistant gram-negative pathogens
针对多重耐药革兰氏阴性病原体的新型基因沉默疗法
- 批准号:
8823180 - 财政年份:2012
- 资助金额:
$ 24.83万 - 项目类别:
Novel gene-silencing therapeutics for multidrug-resistant gram-negative pathogens
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8267916 - 财政年份:2012
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$ 24.83万 - 项目类别:
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