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

描述（由申请人提供）：几种最有希望的1型糖尿病治疗方法的临床实施将需要在体内对人类患者的特定靶细胞进行遗传修饰的能力。胰岛β细胞是最重要的靶点，治疗机会包括诱导再生、抑制自身免疫和上调抗氧化途径。其他几种细胞类型也有可能通过使用转录因子和microrna的定向命运转换被重新编程为功能性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。本申请的目标是开发重组腺相关病毒（rAAV）载体，能够有效和特异性地将遗传有效载荷传递给人类的这些靶细胞。rAAV已被用于几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的rAAV衣壳与基因调控元件（启动子、增强子和microRNA结合位点）结合，将基因表达限制在靶细胞中，可以实现所需的基因传递精度。rAAV衣壳和调控序列将利用异种移植模型优化每种人类细胞类型。

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.