Recombinant human CC10 protein for treatment and prevention of chronic lung allograft dysfunction
重组人 CC10 蛋白用于治疗和预防慢性同种异体肺移植功能障碍
基本信息
- 批准号:10602077
- 负责人:
- 金额:$ 26.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-05 至 2024-08-04
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAirway FibrosisAllograftingAnimal ModelAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAntioxidantsBiochemicalBiologicalBiological AssayBiological Response Modifier TherapyBone Marrow TransplantationBronchiolitis ObliteransCellsChronicChronic Obstructive Pulmonary DiseaseChronic lung diseaseClinicalClinical ManagementClinical TrialsCystic FibrosisDataDevelopmentDoseEpithelial CellsEventFibrosisFunctional disorderFutureGoalsHealthHistopathologyHost DefenseHumanIL8 geneImmuneIn VitroIndividualInfectionInflammationInflammatoryInhalationInhalation ExposureInjuryLifeLongevityLungLung TransplantationLung diseasesMediatingMediatorMethodsModelingMusNeutrophiliaOutcomePathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhasePhenotypePhosphorylationPhysiologyPlayPremature InfantPreparationPreventionProceduresProcessProductionProtein IsoformsProteinsPulmonary FibrosisPulmonary HypertensionPulmonary InflammationReactive Oxygen SpeciesRecombinantsResearchRespiratory FailureRespiratory MucosaRespiratory distressRoleRouteSecretory CellSignal TransductionSmall Business Innovation Research GrantStructure of parenchyma of lungSupplementationT cell responseTNF geneTestingTherapeuticTransgenic OrganismsTransplant RecipientsWorkadaptive immune responseairway epitheliumairway remodelingcell injurycell regenerationcell typeclinical developmentdesigndonor-specific antibodyepithelial repairepithelium regenerationexperiencegain of functionidiopathic pulmonary fibrosisimmunogenicityimmunoregulationimprovedin vitro Assayin vivoinjured airwaylung allograftmouse modelneutrophilnovelnovel therapeutic interventionnovel therapeuticsoxidationp65post-transplantpreventrecruitresponsescale upsecretory proteintherapeutically effectivetransplant modelwasting
项目摘要
Abstract
Over 5,000 lung transplants (LTx) are performed in the US each year to save the lives of patients
in respiratory failure due to COPD, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary
hypertension, and other terminal lung conditions. The vast majority of LTx, long-term survival is
significantly limited by chronic lung allograft dysfunction (CLAD) with a median survival of 6 years
post-transplant. New therapies are urgently needed to improve clinical outcomes in LTx and
CLAD. Native CC10/SCGB1A1 is an important host defense, immunomodulatory, and
homeostatic protein in the lungs, which is known to be deficient in CLAD. Recombinant human
CC10 protein (rhCC10) can augment native CC10 levels in vivo and is a biologic candidate
potentially to treat and prevent CLAD. It has shown efficacy in decreasing lung histopathology in
a murine models of; 1) orthotopic lung transplant model of CLAD, 2) bronchiolitis obliterans
caused by orthotopic bone marrow transplant, in addition to reducing pulmonary inflammation and
fibrosis in several other animal models of acute lung injury and pulmonary fibrosis. RhCC10 was
also shown to be safe in 3 human studies and showed potent anti-inflammatory effects in the
lungs of severely premature infants experiencing respiratory distress. In CLAD patients, the
optimal route of administration is by inhalation, however, inhalation is an inherently inefficient
delivery method. Up to 70% of each drug dose may be wasted, therefore, it is advantageous to
optimize drug potency to enable production and delivery of sufficient quantities to impact clinical
endpoints. Our group has developed methods to enhance the potency of rhCC10 and the
proposed studies will scale-up these methods, characterize the resulting products, and optimize
them for maximal anti-inflammatory activity to lay groundwork for in vivo studies of preparations
with enhanced potency.
抽象的
每年在美国进行超过5,000次肺移植(LTX),以挽救患者的生命
由于COPD引起的呼吸衰竭,特发性肺纤维化,囊性纤维化,肺
高血压和其他末端肺条件。绝大多数LTX,长期生存是
受到慢性肺同种异体功能障碍(CLAD)的限制,中位生存期为6年
移植后。迫切需要新疗法来改善LTX的临床结果和
外壳。本地CC10/SCGB1A1是重要的宿主防御,免疫调节性,并且
肺中的稳态蛋白质稳态,已知甲壳不足。重组人
CC10蛋白(RHCC10)可以在体内增强本地CC10水平,并且是生物学候选者
有可能治疗和防止外壳。它显示出降低肺组织病理学的功效
鼠模型; 1)甲壳的原位肺移植模型,2)支气管炎闭塞
由原位骨髓移植引起的,除了减少肺部炎症和
其他几种急性肺损伤和肺纤维化的动物模型中的纤维化。 RHCC10是
在3项人类研究中也证明是安全的,并显示出有效的抗炎作用
严重过早的婴儿肺部患有呼吸窘迫。在外壳患者中,
最佳给药途径是通过吸入,吸入本质上是一种固有的效率低下
递送方法。每种药剂量的多达70%可能会浪费,因此,这是有利的
优化药物效力,使能够产生和交付足够的数量来影响临床
端点。我们的小组已经开发了提高RHCC10和的方法
拟议的研究将扩展这些方法,表征所得的产品并优化
它们具有最大的抗炎活性,以奠定基础,以进行体内研究
具有增强的效力。
项目成果
期刊论文数量(0)
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APRILE L PILON其他文献
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