In vivo targeting of diabetes-relevant human cell types with rAAV vectors

rAAV 载体体内靶向糖尿病相关人类细胞类型

基本信息

批准号：
8812513
负责人：
Markus Grompe
金额：
$ 360.47万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812513
关键词：
Acinar Cell Alkaline Phosphatase Alpha Cell Antioxidants Autoimmunity Automobile Driving Beta Cell Biliary Binding Binding Sites CDKN1C gene Capsid Cells Clinical Code Complementary DNA DNA Polymerase II DNA Shuffling Diabetes Mellitus Duct (organ) structure Ductal Epithelium Elements Enhancers Epithelium Evolution Gallbladder Gene Delivery Generations Genes Genetic Genetic Transcription Genome Goals Hepatocyte Human Insulin-Dependent Diabetes Mellitus Libraries Liver Methods MicroRNAs Modification Mutation Natural regeneration Pancreas Pancreatic delta Cell Pathway interactions Patients Property Proteins RNA RNA Sequences Reagent Recombinant adeno-associated virus (rAAV)Regulatory Element Safety Specificity Structure of beta Cell of islet Up-Regulation Variant Viral Vector Xenograft Model Xenograft procedure adeno-associated viral vector cell type cellular transduction clinically relevant gene therapy in vivo mutant neutralizing antibody novel oval cell progenitor promoter public health relevance small hairpin RNA therapeutic DNA therapeutic target transcription factor transcriptome sequencing vector

Acinar Cell Alkaline Phosphatase Alpha Cell Antioxidants Autoimmunity Automobile Driving Beta Cell Biliary Binding Binding Sites CDKN1C gene Capsid Cells Clinical Code Complementary DNA DNA Polymerase II DNA Shuffling Diabetes Mellitus Duct (organ) structure Ductal Epithelium Elements Enhancers Epithelium Evolution Gallbladder Gene Delivery Generations Genes Genetic Genetic Transcription Genome Goals Hepatocyte Human Insulin-Dependent Diabetes Mellitus Libraries Liver Methods MicroRNAs Modification Mutation Natural regeneration Pancreas Pancreatic delta Cell Pathway interactions Patients Property Proteins RNA RNA Sequences Reagent Recombinant adeno-associated virus (rAAV)Regulatory Element Safety Specificity Structure of beta Cell of islet Up-Regulation Variant Viral Vector Xenograft Model Xenograft procedure adeno-associated viral vector cell type cellular transduction clinically relevant gene therapy in vivo mutant neutralizing antibody novel oval cell progenitor promoter public health relevance small hairpin RNA therapeutic DNA therapeutic target transcription factor transcriptome sequencing vector

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项目摘要

DESCRIPTION (provided by applicant): Clinical implementation of several of the most promising approaches to the treatment of type 1 diabetes will require the ability to perform genetic modifications of specific target cells in human patients in vivo. The pancreatic beta-cell is the most important target and therapeutic opportunities include the induction of regeneration, suppression of autoimmunity and upregulation of anti-oxidant pathways. Several other cell types have potential to be reprogrammed to functional beta-cells by directed fate conversion using transcription factors and microRNAs. This list includes pancreatic acinar cells, biliary duct epithelium of the liver, gall bladder epithelium, pancreatic delta-cells and alpha-cells. The goal f this application is to develop recombinant adeno-associated virus (rAAV) vectors capable of delivering genetic payloads to these target cells in humans efficiently and specifically. rAAV is already being used in several clinical gene therapy applications and has a good safety record. The required precision of gene delivery will be achieved by combining cell-type specific rAAV capsids with gene regulatory elements (promoters, enhancers and microRNA binding sites) that limit expression to only the target cell. rAAV capsid and the regulatory sequences will be optimized for each human cell type using xenograft models.

描述（由申请人提供）：1型糖尿病治疗的几种最有前途的方法的临床实施将需要对体内人类患者特定靶细胞进行遗传修饰的能力。胰腺β细胞是最重要的目标，治疗机会包括诱导再生，自身免疫性和抗氧化途径的上调。其他几种细胞类型的潜力可以通过使用转录因子和microRNA的定向命运转换将其重新编程为功能性β细胞。该列表包括胰腺腺泡细胞，肝管上皮，胆囊上皮，胰腺纤维细胞和α细胞。该应用的目标是开发重组腺相关病毒（RAAV）向量，能够有效，特别是在人类中向这些目标细胞传递基因有效载荷。 RAAV已经用于多种临床基因治疗应用，并且具有良好的安全记录。基因输送所需的精度将通过将细胞类型的特异性RAAV衣壳与基因调节元件（启动子，增强子和microRNA结合位点）相结合，仅将表达限制在目标细胞中。 RAAV CAPSID和调节序列将使用异种移植模型为每种人类细胞类型进行优化。