Crystalline Endolysin Treatment for Tuberculosis in TB/HIV co-infected patients
结晶内溶素治疗结核病/艾滋病毒合并感染患者的结核病
基本信息
- 批准号:8140918
- 负责人:
- 金额:$ 24.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdultAnimal ModelAntibiotic TherapyAntibodiesAntimicrobial ResistanceAreaArginineAttentionBCG VaccineBacteriaBacteriophagesBindingBiological AssayCanis familiarisCause of DeathCell LineCellsCessation of lifeCharacteristicsChemicalsChildhoodChinaClinical TrialsCommunicable DiseasesComplexCrystal FormationCrystallizationCytolysisDevelopmentDiagnosisDiagnosticDiseaseDisease OutbreaksDrug FormulationsDrug Resistant TuberculosisDrug resistanceEffectivenessEngineeringEnzymesEscherichia coliEsterase GeneExhibitsExtreme drug resistant tuberculosisFeasibility StudiesFibroblastsGoalsGrantHIVHumanImmigrantImmune systemImmunityImmunocompromised HostIn VitroIndiaInfectionLeadLipaseLongevityLungMeasuresModelingModificationMothersMultidrug-Resistant TuberculosisMycobacteriophagesMycobacterium tuberculosisNational Institute of Diabetes and Digestive and Kidney DiseasesNatureOrganismParticulatePatientsPeptide HydrolasesPeptidesPharmaceutical PreparationsPharmacologic SubstancePhasePopulationPreventivePropertyProteinsPulmonary TuberculosisRecombinantsReportingResearchRouteRussiaSaltsSiteSolubilityStructureSystemTechnologyTemperatureTestingThioglycosidesTimeTreatment EfficacyTuberculosisUnited StatesUnited States National Institutes of HealthVaccinesWorld Health Organizationbasecell typechronic pancreatitisdistilled alcoholic beverageefficacy testingendolysinenzyme therapyethnic minority populationexpression cloningglobal healthhuman CREB1 proteinin vivoinner citykillingsmacrophagemortalitynovelphase 1 studypolyanionpolycationpreventprotein Bprototyperesistant straintuberculosis treatment
项目摘要
DESCRIPTION (provided by applicant): Though often considered to be a disease of the past, tuberculosis (TB) is still a leading killer of people worldwide. At the end of 2008, approximately 2 billion people one-third of the world's population is infected with Mycobacterium tuberculosis (MTb), the etiologic agent of TB. The World Health Organization estimates that 2 million people worldwide die of TB each year. TB is now the second most common cause of death from infectious disease in the world after human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). In the mid-1980s, a resurgence of outbreaks in the United States brought renewed attention to TB. Main reasons for increase in TB cases are due to higher vulnerability of people infected with HIV/AIDS and development of drug-resistant strains of MTb, which causes TB in human. In the latest 2010 April WHO report results show that one in every 4 TB patients diagnosed with MDR-TB in Russia and about 50% of MDR-TB burden is in China and India. Worldwide there are 440,000 MDR-TB cases and 150,000 deaths occurred in 2008. About 5.4% of MDR-TB cases have XDR-TB according to the report in March 2010.It is impractical to eliminate TB without novel, and more effective drugs, diagnostics and vaccines. The world immediately needs simpler and faster curative drugs; safer and effective drugs that can treat all forms of TB especially in immuno- compromised people with HIV/TB co-infections. As an alternative to antibiotic therapy, especially for systemic lung infections by M. tuberculosis, we are proposing to develop an enzyme therapy that can be used with various formulation conditions and delivery routes. The enzyme therapy may be as effective as antibiotic therapy because the enzyme is highly specific, and potent against the targeted bacteria. However, delivering these enzymes to the site of the infection remains a challenge. Most pharmaceutical proteins are susceptible to degradation at the site of administration, whether administered intravenously, subcutaneously, orally, topically or by any other route. We believe that a safe and effective delivery system for this application may be through the use of protein crystals, which provides highly concentrated, stable, and pure products. In addition, technologies are also needed to deliver endolysin to intracellular compartment since M. tuberculosis resides in macrophages. Cell penetrating peptides (CPP), either engineered in-frame or adsorbed/bound non-covalently to protein substrates, have been used to deliver a wide variety of molecules into a number of cell types. In this proposal we are proposing to develop a crystalline formulated recombinant endolysin therapy with cell-penetrating peptides (CPP) that can be used with various formulation conditions and delivery routes. The opportunities for CPP conjugated to endolysin are multiple since it may be able to penetrate the macrophages thereby able to kill M. tuberculosis in HIV/TB co-infected patients and may extend their life span with minimal discomfort. In Phase I, we intend to study the feasibility of using endolysins, both soluble and crystalline formulations with or without cell penetrating peptides, as a systemic delivery system in an in vivo animal model for M. tuberculosis infection. If successful, this approach will lead to the introduction of novel, efficient enzyme therapy for the treatment of M. tuberculosis infections.
PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is one of the most devastating global health problems of our time, causing approximately 2 million deaths a year. As a preventive measure, currently BCG vaccine is used to avoid serious complications of TB and to reduce the rate of pediatric TB but It has little or no effectiveness for pulmonary TB in adults. We are proposing a novel crystalline endolysin that is pure, safe, effective even in immunocompromised patients, and unlike vaccines which needs immune system to generate the antibodies the endolysin can act directly on the Mycobacterium tuberculosis organism and thus prevent and treat tuberculosis in HIV/TB co-infected patients.
描述(申请人提供):尽管结核病通常被认为是一种过去的疾病,但它仍然是世界范围内人们的头号杀手。2008年底,约有20亿人感染了结核病的病原体--结核分枝杆菌(MTB),占世界人口的三分之一。世界卫生组织估计,全球每年有200万人死于结核病。结核病现在是仅次于人类免疫缺陷病毒/获得性免疫缺陷综合征(艾滋病毒/艾滋病)的世界第二大传染病死亡原因。20世纪80年代中期,美国再次爆发结核病疫情,重新引起了人们对结核病的关注。结核病病例增加的主要原因是艾滋病毒/艾滋病感染者的易感性增加,以及结核分枝杆菌耐药株的发展,这种菌株会导致人类结核病。在世卫组织最新的2010年4月报告中,结果显示,在俄罗斯,每4名被诊断为耐多药结核病的患者中就有一名,约50%的耐多药结核病负担在中国和印度。2008年,全世界有44万耐多药结核病病例,15万人死亡。根据2010年3月的报告,大约5.4%的耐多药结核病病例患有广泛耐药结核病。如果没有新的、更有效的药物、诊断和疫苗,消除结核病是不切实际的。世界迫切需要更简单、更快速的治疗药物;能够治疗各种形式结核病的更安全、更有效的药物,特别是对免疫功能受损的艾滋病毒/结核病混合感染者。作为抗生素疗法的替代疗法,特别是针对结核分枝杆菌引起的系统性肺部感染,我们建议开发一种酶疗法,这种疗法可以在不同的配方条件和传递途径下使用。酶疗法可能与抗生素疗法一样有效,因为这种酶具有高度的特异性,并且对目标细菌有效。然而,将这些酶输送到感染部位仍然是一个挑战。大多数药物蛋白质在给药部位容易降解,无论是静脉给药、皮下给药、口服、局部给药或任何其他途径。我们认为,使用蛋白质晶体可以提供高度浓缩、稳定和纯净的产品,从而为这一应用提供安全和有效的输送系统。此外,由于结核分枝杆菌驻留在巨噬细胞内,因此还需要将内溶素输送到细胞内的技术。细胞穿透肽(CPP),无论是框内构建的,还是非共价吸附/结合在蛋白质底物上的,都被用来将各种各样的分子输送到多种细胞类型。在这项提案中,我们建议开发一种晶体配方的重组内溶素疗法,它带有细胞穿透肽(CPP),可以在不同的配方条件和给药途径下使用。CPP与内溶素结合的机会是多方面的,因为它可能能够穿透巨噬细胞,从而能够杀死艾滋病毒/结核病混合感染患者的结核分枝杆菌,并可能以最小的不适延长他们的生命。在第一阶段,我们打算研究使用内毒素作为体内结核分枝杆菌感染动物模型的全身给药系统的可行性,包括含有或不含有细胞穿透肽的可溶性和结晶性制剂。如果成功,这种方法将导致引入新的、有效的酶疗法来治疗结核分枝杆菌感染。
公共卫生相关性:结核病是我们这个时代最具破坏性的全球健康问题之一,每年造成约200万人死亡。作为一种预防措施,目前卡介苗被用于避免结核病的严重并发症,降低儿童结核病的发病率,但它对成人肺结核的效果很小或没有效果。我们正在提出一种新的结晶内毒素,它即使在免疫功能低下的患者中也是纯净、安全、有效的,而且与需要免疫系统产生抗体的疫苗不同,内毒素可以直接作用于结核分枝杆菌有机体,从而预防和治疗HIV/TB混合感染患者的结核病。
项目成果
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BHAMI SHENOY其他文献
BHAMI SHENOY的其他文献
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{{ truncateString('BHAMI SHENOY', 18)}}的其他基金
Crystalline Endolysin Treatment for Tuberculosis in TB/HIV co-infected patients
结晶内溶素治疗结核病/艾滋病毒合并感染患者的结核病
- 批准号:
8241931 - 财政年份:2011
- 资助金额:
$ 24.12万 - 项目类别:
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