Oral Protein Therapeutics Against C. difficile Associated Colitis
针对艰难梭菌相关结肠炎的口服蛋白质疗法
基本信息
- 批准号:10455793
- 负责人:
- 金额:$ 74.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAftercareAnaerobic BacteriaAnimalsAnkyrin RepeatAntibiotic ResistanceAntibioticsAntibodiesBacillusBacteriaBindingBloodCattleCecumCell WallCell membraneCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeChloroplastsClinicalClostridium difficileColitisColonColostrumComplementComplexCrystallizationDiarrheaDigestionDiseaseDoseElderlyEncapsulatedEngineeringEnteralEnzymesEpitopesEscape MutantEscherichia coliExhibitsExotoxinsFDA approvedGastrointestinal DiseasesGastrointestinal tract structureGenetic EngineeringGoalsHospitalsImmune systemIn SituIn VitroInfectionInflammatory Bowel DiseasesIntravenousLeadLettuce - dietaryLinkLocationMonoclonal AntibodiesMusOralPathogenesisPathologyPatientsPeptide HydrolasesPharmaceutical PreparationsPhasePlantsProbioticsProtein EngineeringProtein SecretionProteinsPseudomembranous ColitisPublic HealthRecurrenceRelapseReportingReproduction sporesResistanceRibotypesSaccharomycesScaffolding ProteinSeveritiesShiga ToxinStomachStreamStructureSymptomsTherapeuticToxinTreatment outcomeViralVirulence FactorsYeastsabsorptionalpha Toxinantitoxinbasecommensal bacteriacostdesigneffective therapyengineering designfecal transplantationgastrointestinalgastrointestinal infectionimprovedin vivoinsightintravenous administrationmicroorganismneutralizing antibodynext generationpre-clinicalpreservationpressurepreventrecurrent infectionresistance genescaffoldside effectsmall moleculestandard of carestemsuccesstherapeutic proteinthermostability
项目摘要
Abstract
Each year, Clostridium difficile (C. difficile), a Gram-positive, spore-forming anaerobic bacillus, causes over a
quarter million infections, ~15,000 deaths and over $1 billion in treatment-associated costs. The symptoms of
C. difficile infection (CDI) ranges from mild cases of diarrhea to fatal pseudomembranous colitis. Although
primary CDI can generally be treated with antibiotics, over the past decades, the rate of CDI recurrence has
greatly increased due to the emergence of antibiotic-resistant and so-called hypervirulent strains (20-25%
relapse). C. difficile secreted toxin A (TcdA) and toxin B (TcdB) are the critical virulence factors that cause a
range of diseases collectively designated as CDI. The most recently FDA approved CDI therapeutic –
ZINPLAVA (bezloxumab, an intravenously administered anti-TcdB monoclonal antibody to be used concurrent
with antibiotics) – was found to reduce the rate of recurrence but neither lessen the severity nor shorten the
duration of CDI. Thus, more effective therapies against CDI are still urgently needed. Since C. difficile and its
secreted toxins reside within the gastrointestinal (GI) tract, a location not easily accessible by i.v.-administered
antibodies, we hypothesize that an oral toxin-neutralizer should be more effective at preventing CDI
pathogenesis. Previously, anti-toxin hyperimmune bovine colostrum (HBC) has been demonstrated as an
effective oral therapeutic for treating and/or preventing various viral and bacterial GI infections, setting a
precedent for oral anti-toxin protein therapeutics against CDI. Recently, our lab engineered a panel of designed
ankyrin repeat protein (DARPin) with potent neutralization activity against TcdB. The DARPin protein scaffold
was further engineered to render it highly resistant to digestion by GI-resident proteases while retaining its
toxin-neutralization ability. In this project, we intend to further evaluate the therapeutic potential of DARPins
against CDI. Specifically, in Aim 1, to facilitate more effective in situ delivery of anti-toxin DARPins to the
colon, lead probiotic strains will be created for DARPin secretion. In Aim 2, for patients with severely
compromised immune system and unfit for receiving live microorganisms, an alternative cecum/colon protein
delivery strategy will be explored. Concurrently, additional DARPins will be engineered to target highly
conserved domains on TcdA and TcdB (Aim 3). Successful completion of the proposed study will yield anti-
toxins as potential next-generation oral therapeutics against CDI. In addition, this study may establish a new
oral therapeutic paradigm for other enteric diseases.
摘要
项目成果
期刊论文数量(0)
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Zhilei Chen其他文献
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{{ truncateString('Zhilei Chen', 18)}}的其他基金
A Novel Technology for Engineering Binders to Membrane Proteins
膜蛋白结合剂工程新技术
- 批准号:
10040547 - 财政年份:2020
- 资助金额:
$ 74.77万 - 项目类别:
A Novel Technology for Engineering Binders to Membrane Proteins
膜蛋白结合剂工程新技术
- 批准号:
10227122 - 财政年份:2020
- 资助金额:
$ 74.77万 - 项目类别:
Internal Toxin Neutralizer for Treating STEC-infection
用于治疗 STEC 感染的内毒素中和剂
- 批准号:
9886184 - 财政年份:2019
- 资助金额:
$ 74.77万 - 项目类别:
Artificial Ecology Sink as prophylaxis against viral infection
人工生态水槽预防病毒感染
- 批准号:
9348755 - 财政年份:2017
- 资助金额:
$ 74.77万 - 项目类别:
Broadly neutralizing non-antibody protein for treating clostridium difficile infection
用于治疗艰难梭菌感染的广泛中和非抗体蛋白
- 批准号:
9293991 - 财政年份:2016
- 资助金额:
$ 74.77万 - 项目类别:
Broadly neutralizing non-antibody protein for treating clostridium difficile infection
用于治疗艰难梭菌感染的广泛中和非抗体蛋白
- 批准号:
9167525 - 财政年份:2016
- 资助金额:
$ 74.77万 - 项目类别:
Isolation of Genetic Suppressor Elements Against Hepatitis C Virus
抗丙型肝炎病毒基因抑制元件的分离
- 批准号:
7905080 - 财政年份:2009
- 资助金额:
$ 74.77万 - 项目类别:
Isolation of Genetic Suppressor Elements Against Hepatitis C Virus
抗丙型肝炎病毒基因抑制元件的分离
- 批准号:
7708619 - 财政年份:2009
- 资助金额:
$ 74.77万 - 项目类别:
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