Novel Strategies to Clear Bacteria from the CF Lung
清除 CF 肺细菌的新策略
基本信息
- 批准号:10751325
- 负责人:
- 金额:$ 9.47万
- 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:2023-03-24 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAwardBacteriaBacterial InfectionsBirthBloodBusinessesCareer MobilityCell membraneCellsChronicCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCystic Fibrosis sputumDataDehydrationDevelopmentDoseDrug KineticsGenesGenetic DiseasesGlosso-SterandrylImmuneImmune responseImmunocompromised HostInflammationInflammatory ResponseInhalationKnowledgeLeukocyte ElastaseLiquid substanceLungLung infectionsMentorsModelingMucous body substanceMusMutationNasal EpitheliumNeutrophiliaNonsense MutationNormal RangePalatePatientsPeptide HydrolasesPeptidesPeripheralPharmacologic SubstancePlayPredispositionProtein SecretionPseudomonas aeruginosaPulmonary Cystic FibrosisPulmonary Function Test/Forced Expiratory Volume 1Pulmonary InflammationRattusRegulator GenesRoleStaphylococcus aureusTrainingWorkchronic infectioncystic fibrosis airwaycystic fibrosis mousecystic fibrosis patientscytokinedisease-causing mutationdrug developmentexperienceexperimental studyimprovedlung healthlung injuryneutrophilnovelnovel strategiespathogenpeptidomimeticspulmonary function
项目摘要
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis
transmembrane regulator (CFTR) gene. CF airways are immunocompromised and
become colonized with bacteria soon after birth. Chronic bacterial infection leads to
persistent and severe neutrophil-dominated pulmonary inflammation, high lung protease
levels, lung damage and a decline in FEV1. CFTR modulator/correctors from Vertex
increase CF patient lung function but do not bring it into the normal range, do not treat
CF patients with nonsense mutations and for patients with pre-existing bacterial lung
infections, do not clear bacteria from their lungs. Thus, there is a critical unmet need for
novel, CFTR mutation-agnostic therapies to help clear bacteria from CF lungs and limit
neutrophilic lung damage. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1)
is a secreted protein that is highly expressed in the lung, where it plays a key role in
maintaining lung health. SPLUNC1 is a CF gene modifier, and patients with reduced
SPLUNC1 levels have lower FEV1 and exacerbate more frequently. SPUNC1 inhibits
Orai1, a ubiquitously expressed plasma membrane Ca2+ channel that regulates
inflammation. However, SPLUNC1 is rapidly degraded by neutrophil elastase (NE),
which we posit results in greater Orai1 activity and more inflammation. Consistent with
this, our preliminary data indicate that Orai1 is upregulated in CF patient lung immune
cells. Given Orai1’s proximal role in the immune response, Orai1 is thus an attractive
target whose inhibition is predicted to help resolve CF inflammation. Eldec Pharma has
developed a robust, novel peptidomimetic called ELD607, which reprises SPLUNC1’s
ability to inhibit Orai1, yet is significantly more stable in the presence of NE, and
significantly more potent/efficacious. ELD607 is stable in proteolytic CF sputum and
inhibits Ca2+-influx in freshly-isolated CF patient peripheral neutrophils and in CF
sputum-derived immune cells in a mutation-agnostic fashion. In murine lung infection
models with common CF pathogens including P. aeruginosa and S. aureus, a single,
inhaled dose of ELD607 reduced lung inflammation (neutrophilia, cytokines, NE) by
90%, decreased lung bacterial infection by 3-4 log10 CFUs and increased survival. In a
chronic CF model (SCNN1B mice), ELD607 reduced neutrophilia and increased
survival. These experiments demonstrate that rebalancing the lung’s inflammatory
response by inhibiting Orai1 enhances the lungs’ natural ability to clear pathogens. In
this proposal, we will use wild-type and rats to determine the pharmacokinetics of
ELD607 after IV administration and determine its stability in blood. Secondly, we
propose to evaluate whether acute and/or chronic administration of ELD607 reduce
neutrophilia and /or clear bacteria from CF mice lungs. In terms of training and
mentoring, this Diversity Supplement will allow Dr. Sassano to advance her knowledge
in the drug development field, as well as permit her to acquire business and
development experience to advance her career. Given her background, Dr. Sassano is
an excellent candidate to improve diversity at Eldec Pharmaceuticals.
囊性纤维化(CF)是一种由囊性纤维化突变引起的遗传病
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(0)
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Saira Ahmad其他文献
Saira Ahmad的其他文献
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{{ truncateString('Saira Ahmad', 18)}}的其他基金
Novel Peptide Immunomodulators for Treating Sepsis
用于治疗脓毒症的新型肽免疫调节剂
- 批准号:
10602761 - 财政年份:2023
- 资助金额:
$ 9.47万 - 项目类别:
Novel Strategies to Clear Bacteria from the CF Lung
清除 CF 肺细菌的新策略
- 批准号:
10544476 - 财政年份:2022
- 资助金额:
$ 9.47万 - 项目类别:
Novel Strategies to Clear Bacteria from the CF Lung
清除 CF 肺细菌的新策略
- 批准号:
10680454 - 财政年份:2022
- 资助金额:
$ 9.47万 - 项目类别:
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