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
每年,艰难梭菌(C.艰难梭菌),一种革兰氏阳性,孢子形成的厌氧杆菌,
25万例感染,约15,000例死亡和超过10亿美元的治疗相关费用。的症状
C.艰难梭菌感染(CDI)的范围从轻度腹泻到致命的假膜性结肠炎。虽然
原发性CDI通常可以用抗生素治疗,在过去的几十年里,CDI的复发率
由于出现了耐药性和所谓的高毒力菌株,
复发)。C.艰难梭菌分泌的毒素A(TcdA)和毒素B(TcdB)是引起艰难梭菌感染的关键毒力因子。
一系列疾病统称为CDI。最近FDA批准的CDI治疗剂-
ZINPLAVA(bezloxumab,一种静脉给药的抗TcdB单克隆抗体,同时使用
与抗生素)-被发现可以降低复发率,但既不能减轻严重程度,也不能缩短
CDI的持续时间。因此,仍然迫切需要针对CDI的更有效的疗法。自从C.艰难及其
分泌的毒素驻留在胃肠道(GI)内,这是通过i.v.施用
抗体,我们假设口服毒素中和剂应该更有效地预防CDI
发病机制以前,抗毒素超免疫牛初乳(HBC)已被证明是一种
用于治疗和/或预防各种病毒和细菌GI感染的有效口服治疗剂,
这是针对CDI的口服抗毒素蛋白治疗剂的先例。最近,我们的实验室设计了一组
锚蛋白重复序列蛋白(DARPin),其具有针对TcdB的有效中和活性。DARPin蛋白支架
进一步工程化以使其对GI驻留蛋白酶的消化具有高度抗性,同时保留其
毒素中和能力在这个项目中,我们打算进一步评估DARPins的治疗潜力,
反对CDI具体地,在目的1中,为了促进抗毒素DARPin更有效地原位递送至细胞,
结肠,将产生用于DARPin分泌的先导益生菌菌株。在目标2中,对于严重
免疫系统受损,不适合接受活微生物,一种替代盲肠/结肠蛋白
将探讨执行战略。与此同时,更多的DARPin将被设计成高度针对
TcdA和TcdB上的保守结构域(目的3)。成功完成拟议的研究将产生反-
毒素作为对抗CDI的潜在下一代口服治疗剂。此外,这项研究可能会建立一个新的
其他肠道疾病的口服治疗范例。
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)
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Zhilei Chen其他文献
Zhilei Chen的其他文献
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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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