A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
基本信息
- 批准号:10217078
- 负责人:
- 金额:$ 43.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAgonistAlcohol abuseAlcohol consumptionAlcoholsAttenuatedAutologous TransplantationBCHE geneBehaviorBehavioralBrain DiseasesButyrylcholinesteraseCRISPR/Cas technologyCellsClinicalCocaineCocaine AbuseCocaine UsersCounselingCuesCutaneousDevelopmentDoseDoxycyclineDrug AddictionDrug abuseEatingEngineered skinEngineeringEnzymesEthanolExhibitsExposure toFDA approvedFemaleGLP-I receptorGene DeliveryGenesGoalsHepatocyteHumanHuman EngineeringHydrolysisImmune responseImmunocompetentIntravenousMethodsMorbidity - disease rateMusMutagenesisNon-Insulin-Dependent Diabetes MellitusNude MiceOrganPatientsPeripheralPharmaceutical PreparationsPhysiologicalPlasmaPre-Clinical ModelPropertyRelapseResearchResidual stateRiskRodentSelf AdministrationSiteSkinSkin TransplantationSkin graftSubstrate SpecificitySudden DeathSurfaceSystemTestingTherapeuticTherapeutic AgentsTimeTissue EngineeringToxic effectTrainingTransplantationTreatment ProtocolsWorkalcohol relapsealcohol use disorderbehavioral responseblood glucose regulationburn therapyburn woundcell typecocaethyleneconditioned place preferencecostdrug of abuseepidermal stem cellexperiencegene therapyglucagon-like peptide 1help-seeking behaviorin vivoindividual variationinnovationmalemortalitynovelparenteral administrationpreventpreventable deathresponseskin woundstem cellstherapeutic gene
项目摘要
PROJECT SUMMARY
Cocaine and alcohol are commonly abused and frequently co-abused drugs. Available medications do not
meet the needs for treating ongoing cocaine and alcohol abuse, relapse and co-abuse. The modified human
butyrylcholinesterase (hBChE) exhibits great catalytic potency and substrate specificity for cocaine hydrolysis
and is effective in reducing the behavioral and toxic effects of cocaine in rodents. The glucagon-like peptide 1
(GLP1) receptor agonists can attenuate the reinforcing properties of cocaine and alcohol in rodents. Both
hBChE and GLP1 have very short half-lives in vivo, however, limiting their potential in treating cocaine abuse
and co-abuse with alcohol. Cultured epidermal autografts have been clinically used for treatment of massive
skin wounds for decades. Transplantation of skin grafts derived from engineered skin progenitor cells provides
a novel and ideal approach for long-term and efficient delivery of therapeutic agents in vivo. We have made
key technical advancement in developing a novel mouse-to-mouse skin transplantation method that allows the
stable introduction of engineered epidermal progenitor cells into immunocompetent host mice. We have also
used the CRISPR technology to target either an hBChE gene or a doxycycline (dox)-inducible modified GLP1
gene (DImGLP1) into epidermal progenitor cells. We then transplanted the engineered hBChE or DImGLP1
cells into mice either separately (GhBChE and GDImGLP1) or together (GBChEGLP1). GhBChE and
GDImGLP1 mice did not develop cocaine- and ethanol-induced conditioned place preference (CPP)
respectively. Grafting hBChE cells right after CPP expression attenuated cocaine-induced reinstatement of
CPP. GBChEGLP1 mice did not develop CPP and they exhibited a lower lethality rate induced by cocaine and
ethanol co-administration than those in control mice. The goal of this proposal is to take advantage of these
novel platforms to test an innovative cutaneous gene therapy for cocaine abuse and co-abuse with alcohol in
mice. We will also evaluate duration of hBChE and mGLP1 protection against cocaine and/or alcohol abuse,
potential immune responses and approaches to reduce them. We expect the proposed cutaneous gene
therapy to be long-lasting, highly specific and efficient with little individual variation. To be able to engineer
stable in vivo bio-delivery systems for therapeutic genes via epidermal progenitor cells is significant
because it holds potential for reducing ongoing cocaine abuse and co-abuse with alcohol and relapse
in users and addicts. The proposed work will have a high impact in that results will lay key
groundwork for the development of a highly personalized, long-lasting and affordable approach for
combating cocaine abuse and co-abuse with alcohol.
项目摘要
可卡因和酒精是常见的滥用药物,并且经常合并滥用。现有的药物不
满足治疗持续的可卡因和酒精滥用、复吸和共同滥用的需要。的经修饰的人
丁酰胆碱酯酶(hBChE)对可卡因的水解具有很强的催化活性和底物特异性
并有效降低可卡因对啮齿动物的行为和毒性作用。胰高血糖素样肽1
(GLP 1)受体激动剂可以减弱可卡因和酒精在啮齿类动物中的强化特性。两
然而,hBChE和GLP 1在体内的半衰期非常短,限制了它们治疗可卡因滥用的潜力
和酒精滥用。培养的自体表皮移植物已在临床上用于治疗巨大的
几十年的皮肤创伤。来自工程化皮肤祖细胞的皮肤移植物的移植提供了
一种用于治疗剂在体内的长期和有效递送的新的和理想的方法。我们取得了
在开发一种新的小鼠对小鼠皮肤移植方法方面的关键技术进步,
将工程化表皮祖细胞稳定引入免疫活性宿主小鼠。我们还
使用CRISPR技术靶向hBChE基因或多西环素(dox)诱导的修饰GLP 1
基因(DImGLP1)导入表皮祖细胞。然后,我们将工程化的hBChE或DImGLP1
将细胞分别(GhBChE和GDImGLP1)或一起(GBChEGLP 1)植入小鼠。GhBChE和
GDImGLP1小鼠未出现可卡因和乙醇诱导的条件性位置偏爱(CPP)
分别在CPP表达后立即移植hBChE细胞可减弱可卡因诱导的神经功能恢复
CPP。GBChEGLP 1小鼠没有产生CPP,并且它们表现出较低的可卡因诱导的致死率,
与对照小鼠相比,乙醇联合给药。该提案的目标是利用这些
新的平台来测试一种创新的皮肤基因疗法,用于治疗可卡因滥用和与酒精共滥用,
小鼠我们还将评估hBChE和mGLP 1对可卡因和/或酒精滥用的保护作用的持续时间,
潜在的免疫反应和减少它们的方法。我们希望提出的皮肤基因
治疗是持久的,高度特异性和有效的,几乎没有个体差异。能够设计
通过表皮祖细胞的治疗基因的稳定的体内生物递送系统是重要的
因为它有可能减少持续的可卡因滥用和与酒精和复发的共同滥用
吸毒者和瘾君子拟议的工作将产生很大影响,因为结果将成为关键
为制定高度个性化、持久和负担得起的方法奠定基础,
打击可卡因滥用和与酒精同时滥用。
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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Xiaoyang Wu其他文献
Xiaoyang Wu的其他文献
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{{ truncateString('Xiaoyang Wu', 18)}}的其他基金
Development of a novel lymphocyte engineering approach for treatment of vitiligo
开发治疗白癜风的新型淋巴细胞工程方法
- 批准号:
10640098 - 财政年份:2022
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10017029 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
9762266 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10666502 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10456838 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
Development of epidermal progenitor cell-based therapy for regenerative medicine
开发基于表皮祖细胞的再生医学疗法
- 批准号:
10091532 - 财政年份:2017
- 资助金额:
$ 43.74万 - 项目类别:
Development of epidermal progenitor cell-based therapy for regenerative medicine
开发基于表皮祖细胞的再生医学疗法
- 批准号:
9280088 - 财政年份:2017
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞的协调细胞骨架动力学 - 重新提交 01
- 批准号:
9327655 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞中协调的细胞骨架动力学 - 重新提交 01
- 批准号:
8735610 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞的协调细胞骨架动力学 - 重新提交 01
- 批准号:
8625508 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
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