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

• 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
• 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

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）：几种最有前途的 1 型糖尿病治疗方法的临床实施需要能够在人类患者体内对特定靶细胞进行基因修饰。胰腺β细胞是最重要的靶标，治疗机会包括诱导再生、抑制自身免疫和上调抗氧化途径。其他几种细胞类型有可能通过使用转录因子和 microRNA 进行定向命运转换而被重编程为功能性 β 细胞。该列表包括胰腺腺泡细胞、肝脏胆管上皮、胆囊上皮、胰腺δ细胞和α细胞。该应用的目标是开发重组腺相关病毒 (rAAV) 载体，能够高效、特异地将遗传有效负载传递到人类的这些靶细胞。 rAAV 已被用于多种临床基因治疗应用，并具有良好的安全记录。通过将细胞类型特异性 rAAV 衣壳与基因调控元件（启动子、增强子和 microRNA 结合位点）相结合，将表达仅限于靶细胞，从而实现所需的基因递送精度。 rAAV 衣壳和调控序列将使用异种移植模型针对每种人类细胞类型进行优化。