腺病毒介导的 TRAIL 基因（Ad5hTRAIL）转染胰岛延长链脲佐菌素诱导糖尿病大鼠的血糖正常化。

Adenovirus-mediated TRAIL gene (Ad5hTRAIL) delivery into pancreatic islets prolongs normoglycemia in streptozotocin-induced diabetic rats.

机构信息

Human Gene Therapy Division, Department of Medical Genetics, Faculty of Medicine, Akdeniz University, Antalya 07070, Turkey.

出版信息

Hum Gene Ther. 2009 Oct;20(10):1177-89. doi: 10.1089/hum.2009.039.

DOI:10.1089/hum.2009.039

PMID:19572802

Abstract

Type 1 diabetes (T1D), characterized by permanent destruction of insulin-producing beta cells, is lethal unless conventional exogenous insulin therapy or whole-organ transplantation is employed. Although pancreatic islet transplantation is a safer and less invasive method compared with whole-organ transplant surgery, its treatment efficacy has been limited by islet graft malfunction and graft failure. Thus, ex vivo genetic engineering of beta cells is necessary to prolong islet graft survival. For this reason, a novel gene therapy approach involving adenovirus-mediated TRAIL gene delivery into pancreatic islets was tested to determine whether this approach would defy autoreactive T cell assault in streptozotocin (STZ)-induced diabetic rats. To test this, genetically modified rat pancreatic islets were transplanted under the kidney capsule of STZ-induced diabetic rats, and diabetic status (blood sugar and body weight) was monitored after islet transplantation. STZ-induced diabetic rats carrying Ad5hTRAIL-infected islets experienced prolonged normoglycemia compared with animals grafted with mock-infected or AdCMVLacZ-infected islets. In addition, severe insulitis was detected in animals transplanted with mock-infected or AdCMVLacZ-infected islets, whereas the severity of insulitis was reduced in animals engrafted with Ad5hTRAIL-infected islets. Thus, TRAIL overexpression in pancreatic islets extends allograft survival and function, leading to a therapeutic benefit in STZ-induced diabetic rats.

摘要

1 型糖尿病（T1D）的特征是胰岛素产生细胞的永久性破坏，如果不采用常规的外源性胰岛素治疗或整个器官移植，就会致命。虽然与整个器官移植手术相比，胰岛移植是一种更安全、创伤更小的方法，但由于胰岛移植物功能障碍和移植物衰竭，其治疗效果受到限制。因此，需要对β细胞进行体外基因工程改造，以延长胰岛移植物的存活时间。出于这个原因，测试了一种涉及用腺病毒介导的 TRAIL 基因传递到胰岛的新型基因治疗方法，以确定这种方法是否能抵御链脲佐菌素（STZ）诱导的糖尿病大鼠中的自身反应性 T 细胞攻击。为此，将经过基因修饰的大鼠胰岛移植到 STZ 诱导的糖尿病大鼠的肾包膜下，并在胰岛移植后监测糖尿病状态（血糖和体重）。与用模拟感染或 AdCMVLacZ 感染的胰岛移植的动物相比，携带 Ad5hTRAIL 感染胰岛的 STZ 诱导的糖尿病大鼠经历了更长时间的正常血糖。此外，在接受模拟感染或 AdCMVLacZ 感染的胰岛移植的动物中检测到严重的胰岛炎，而在接受 Ad5hTRAIL 感染的胰岛移植的动物中，胰岛炎的严重程度降低。因此，TRAIL 在胰岛中的过度表达延长了同种异体移植物的存活和功能，在 STZ 诱导的糖尿病大鼠中带来了治疗益处。