MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
修饰聚二硫胺作为胰腺靶向聚合载体
基本信息
- 批准号:8622191
- 负责人:
- 金额:$ 26.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-01 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:Activated LymphocyteAdverse effectsAdverse eventAffinityAminesAnimal BehaviorAnimal ModelAnimalsAttentionAutoimmune DiabetesAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesAziridinesBacterial InfectionsBehaviorBindingBiocompatibleBiological AssayBlood CirculationBlood VesselsBuffersCD4 Positive T LymphocytesCD8B1 geneCell Culture TechniquesCell SurvivalCellsCellular ImmunityCellular StressCessation of lifeChargeChoices and ControlClinical TrialsComplexCystamineCytomegalovirusDataDefense MechanismsDevelopmentDiabetes MellitusDiabetes preventionDiseaseDisulfidesDoseDown-RegulationDrug or chemical Tissue DistributionEffectivenessElectron MicroscopyElectrostaticsEndocytosisEnvironmentEnzyme-Linked Immunosorbent AssayExhibitsFutureGel ChromatographyGene DeliveryGene ExpressionGene TransferGenesGenetic Crossing OverGenetic TranscriptionGoalsHomologous GeneHumanImmune systemIn VitroInbred NOD MiceInjection of therapeutic agentInsulinInsulin-Dependent Diabetes MellitusInterruptionIslet CellIslets of LangerhansKineticsLigandsLymphocyteMajor Histocompatibility ComplexMalignant NeoplasmsMeasuresMediatingMembrane GlycoproteinsMemoryMental DepressionMetricModelingModificationMolecular WeightMusNatural Killer CellsNon obeseOrganPancreasParticle SizePathogenesisPhysical condensationPlasmidsPlayPolymersProteinsRattusReporterReporter GenesReportingResearchRoleSafetySchemeSerumSignal PathwaySpatial DesignStressStructureSurfaceSystemT-LymphocyteTailTestingTherapeuticTissuesTitrationsTransactivationTransfectionTreatment EfficacyTretinoinTumor-DerivedVascular Endothelial CellVeinsViralViral VectorVirus DiseasesWeights and Measuresanalogautoreactive T cellbasebiomaterial compatibilitycell behaviorcytotoxicitydesigndiabeticdosagegene therapyin vivoin vivo Modelinsulin dependent diabetes mellitus onsetintravenous administrationisletlight scatteringmetaplastic cell transformationneoplastic cellnon-viral gene therapynovelnovel strategiesnovel therapeutic interventionp65particleplasmid DNApolymerizationpreventpromoterprotein expressionpublic health relevancereceptorresearch studytherapeutic targettraffickingtranscription factortumortype I diabeticvectorzeta potential
项目摘要
DESCRIPTION (provided by applicant): Recently, non-viral gene therapy continues to attract much attention due to increasing safety concerns and deleterious adverse events of viral vectors in clinical trials. The goal of this application is to design a functional, pancreas-targeting polymeric gene carrier to carry therapeutic plasmid DNAs for efficient type-1 diabetes gene therapy. A new class of biodegradable polymeric carriers based on poly(disulfide amine)s are proposed. Poly(disulfide amine)s have demonstrated higher transfection efficiency with much lower cytotoxicity compared to conventional high molecular weight polyethylenimine. These biodegradable and biocompatible poly(disulfide amine) gene carriers will be modified for active targeting by PEG conjugation bearing ephrine, a pancreas-specific targeting ligand. The use of PEG is two-fold to first provide coronal ephrine presentation and for polyplex stability following intravenous administration. Type-1 diabetes is a deadly disease with numerous deleterious and deadly sequelae; yet, years of mechanistic research has yet to provide a clear pathogenic understanding. It is reported that NKG2D-mediated death of islet 2-cells plays an important role in the pathogenesis of type-1 diabetes. Recent reports demonstrate that tumors prevent attack by the host immune system by secreting soluble ligands for the receptor, NKG2D, expressed in several activated lymphocytes. This ability of tumors to disguise itself leads to reduced cell-cell contact-mediated cytocidal activity of the lymphocytes. Hence, exploiting this tumor model behavior we hypothesize that islet 2-cells secreting this soluble ligand for NKG2, sRAE-1, will protect pancreatic islets from autoimmune lymphocytes. In conjunction with ephrine-targeted poly(disulfide amine) gene carriers to the pancreas, we hypothesize that a pancreas-specific rat insulin promoter (RIP) will provide even tighter spatial and temporal control over sRAE-1 expression. To enhance transcription of sRAE-1, a two-step transcriptional amplification (TSTA) will be used. This novel approach to treat type-1 diabetes will be evaluated in vitro and in vivo with type-1 diabetic, non-obese (NOD) mice.
描述(由申请人提供):近年来,由于临床试验中病毒载体的安全性问题和有害不良事件的增加,非病毒基因治疗继续引起人们的广泛关注。本应用的目标是设计一种功能性的胰腺靶向聚合基因载体,携带治疗性质粒dna,用于有效的1型糖尿病基因治疗。提出了一种新的基于聚二硫胺的可生物降解聚合物载体。与传统的高分子量聚乙烯亚胺相比,聚二硫胺具有更高的转染效率和更低的细胞毒性。这些可生物降解和生物相容性的聚二硫胺基因载体将被PEG偶联修饰为具有活性靶向性的ephrine,一种胰腺特异性靶向配体。PEG的使用有两方面的作用,首先是提供冠状肾上腺素的呈现,以及静脉给药后的复合稳定性。1型糖尿病是一种致命的疾病,有许多有害和致命的后遗症;然而,多年的机制研究尚未提供一个明确的致病认识。据报道,nkg2d介导的胰岛2细胞死亡在1型糖尿病的发病机制中起重要作用。最近的报道表明,肿瘤通过分泌受体的可溶性配体NKG2D来防止宿主免疫系统的攻击,NKG2D在几个活化的淋巴细胞中表达。这种肿瘤伪装自身的能力导致细胞接触介导的淋巴细胞杀伤活性降低。因此,利用这种肿瘤模型行为,我们假设分泌NKG2可溶性配体sRAE-1的胰岛2细胞将保护胰岛免受自身免疫淋巴细胞的攻击。结合胰腺的ephrine靶向多(二硫胺)基因载体,我们假设胰腺特异性大鼠胰岛素启动子(RIP)将对sRAE-1的表达提供更严格的时空控制。为了增强sRAE-1的转录,将使用两步转录扩增(TSTA)。这种治疗1型糖尿病的新方法将在体外和体内用1型糖尿病非肥胖(NOD)小鼠进行评估。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes.
- DOI:10.1016/j.jconrel.2012.08.008
- 发表时间:2012-09-28
- 期刊:
- 影响因子:0
- 作者:Joo WS;Jeong JH;Nam K;Blevins KS;Salama ME;Kim SW
- 通讯作者:Kim SW
EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide-diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets.
- DOI:10.1016/j.jconrel.2011.10.022
- 发表时间:2012-02-28
- 期刊:
- 影响因子:0
- 作者:Blevins KS;Jeong JH;Ou M;Brumbach JH;Kim SW
- 通讯作者:Kim SW
Poly(Amido Amine)s Containing Agmatine and Butanol Side Chains as Efficient Gene Carriers.
- DOI:10.1002/mabi.201500369
- 发表时间:2016-04
- 期刊:
- 影响因子:4.6
- 作者:Won YW;Ankoné M;Engbersen JF;Feijen J;Kim SW
- 通讯作者:Kim SW
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SUNG WAN KIM其他文献
SUNG WAN KIM的其他文献
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{{ truncateString('SUNG WAN KIM', 18)}}的其他基金
Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment
与新型聚合物缀合的用于癌症治疗的溶瘤腺病毒的设计
- 批准号:
8703645 - 财政年份:2013
- 资助金额:
$ 26.68万 - 项目类别:
Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment
与新型聚合物缀合的用于癌症治疗的溶瘤腺病毒的设计
- 批准号:
9273483 - 财政年份:2013
- 资助金额:
$ 26.68万 - 项目类别:
Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment
与新型聚合物缀合的用于癌症治疗的溶瘤腺病毒的设计
- 批准号:
9067328 - 财政年份:2013
- 资助金额:
$ 26.68万 - 项目类别:
Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment
与新型聚合物缀合的用于癌症治疗的溶瘤腺病毒的设计
- 批准号:
8560352 - 财政年份:2013
- 资助金额:
$ 26.68万 - 项目类别:
MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
修饰聚二硫胺作为胰腺靶向聚合载体
- 批准号:
8026857 - 财政年份:2010
- 资助金额:
$ 26.68万 - 项目类别:
MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
修饰聚二硫胺作为胰腺靶向聚合载体
- 批准号:
7767881 - 财政年份:2010
- 资助金额:
$ 26.68万 - 项目类别:
MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
修饰聚二硫胺作为胰腺靶向聚合载体
- 批准号:
8225388 - 财政年份:2010
- 资助金额:
$ 26.68万 - 项目类别:
MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
修饰聚二硫胺作为胰腺靶向聚合载体
- 批准号:
8418704 - 财政年份:2010
- 资助金额:
$ 26.68万 - 项目类别:
FUNCTIONAL AND TARGETING POLYMERIC GENE CARRIERS
功能性和靶向性聚合基因载体
- 批准号:
7729342 - 财政年份:2009
- 资助金额:
$ 26.68万 - 项目类别:
FUNCTIONAL AND TARGETING POLYMERIC GENE CARRIERS
功能性和靶向性聚合基因载体
- 批准号:
7932197 - 财政年份:2009
- 资助金额:
$ 26.68万 - 项目类别:
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