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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：
8026857
负责人：
SUNG WAN KIM
金额：
$ 26.83万
依托单位：
UNIVERSITY OF UTAH
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：
https://reporter.nih.gov/project-details/8026857
关键词：
Activated Lymphocyte Adverse effects Adverse event Affinity Amines Animal Behavior Animal Model Animals Attention Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmune Responses Aziridines Bacterial Infections Behavior Binding Biocompatible Biological Assay Blood Circulation Blood Vessels Buffers CD4 Positive T Lymphocytes CD8B1 gene Cell Culture Techniques Cell Survival Cells Cellular Immunity Cellular Stress Cessation of life Charge Choices and Control Clinical Trials Complex Cystamine Cytomegalovirus Data Defense Mechanisms Development Diabetes Mellitus Diabetes prevention Disease Disulfides Dose Down-Regulation Drug or chemical Tissue Distribution Effectiveness Electron Microscopy Electrostatics Endocytosis Environment Enzyme-Linked Immunosorbent Assay Exhibits Future Gel Chromatography Gene Delivery Gene Expression Gene Transfer Genes Genetic Crossing Over Genetic Transcription Goals Homologous Gene Human Immune system In Vitro Inbred NOD Mice Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Interruption Islet Cell Islets of Langerhans Kinetics Ligands Lymphocyte Major Histocompatibility Complex Malignant Neoplasms Measures Mediating Membrane Glycoproteins Memory Mental Depression Metric Modeling Modification Molecular Weight Mus Natural Killer Cells Non obese Organ Pancreas Particle Size Pathogenesis Physical condensation Plasmids Play Polymers Proteins Rattus Reporter Reporter Genes Reporting Research Role Safety Scheme Serum Signal Pathway Spatial Design Stress Structure Surface System T-Lymphocyte Tail Testing Therapeutic Tissues Titrations Transactivation Transfection Treatment Efficacy Tretinoin Tumor-Derived Vascular Endothelial Cell Veins Viral Viral Vector Virus Diseases Weights and Measures analog autoreactive T cell base biomaterial compatibility cell behavior cytotoxicity design diabetic dosage gene therapy in vivo in vivo Model insulin dependent diabetes mellitus onset intravenous administration islet light scattering metaplastic cell transformation neoplastic cell non-viral gene therapy novel novel strategies novel therapeutic intervention p65 particle plasmid DNA polymerization prevent promoter protein expression public health relevance receptor research study therapeutic target trafficking transcription factor tumor type I diabetic vector zeta 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. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to create a rational, pancreas-specific targeting vehicle for soluble RAE-1 expression to deter autoimmune responses for the treatment of type-1 diabetes.

描述（由申请人提供）：最近，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吸引人们的关注。本申请的目的是设计一种功能性的胰腺靶向聚合物基因载体，以携带用于有效的1型糖尿病基因治疗的治疗性质粒DNA。提出了一类基于聚二硫胺的新型生物可降解聚合物载体。与常规高分子量聚乙烯亚胺相比，聚（二硫胺）已证明具有更高的转染效率和低得多的细胞毒性。这些生物可降解和生物相容的聚（二硫胺）基因载体将被修饰为通过PEG缀合承载胰特异性靶向配体的活性靶向。PEG的使用是双重的，以首先提供冠状动脉递呈和静脉内施用后的复合物稳定性。 1型糖尿病是一种致命的疾病，具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明确的致病性理解。NKG 2D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，肿瘤通过分泌可溶性受体NKG 2D配体来防止宿主免疫系统的攻击，NKG 2D在几种活化的淋巴细胞中表达。这种肿瘤伪装自身的能力导致淋巴细胞的细胞-细胞接触介导的杀细胞活性降低。因此，利用这种肿瘤模型行为，我们假设分泌这种NKG 2的可溶性配体sRAE-1的胰岛2-细胞将保护胰岛免受自身免疫淋巴细胞的侵害。结合肾上腺素靶向聚（二硫胺）基因载体的胰腺，我们假设胰腺特异性大鼠胰岛素启动子（RIP）将提供更严格的空间和时间控制sRAE-1的表达。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。公共卫生相关性：本提案的目的是建立一个合理的，胰腺特异性靶向载体可溶性RAE-1的表达，以阻止自身免疫反应的治疗1型糖尿病。