Gene transfer with A20 to improve islet transplantation

使用 A20 进行基因转移以改善胰岛移植

• 批准号: 6613307
• 负责人: CHRISTIANE FERRAN
• 金额: $ 17万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613307
• 关键词: Adenoviridae; NOD mouse; adeno associated virus group; apoptosis; biotechnology; gene expression; histocompatibility; insulin dependent diabetes mellitus; pancreatic islet transplantation; recombinant virus; streptozotocin; transfection; transplant rejection

DESCRIPTION (provided by applicant): Islet cell transplantation for patients with type I autoimmune diabetes has the potential to cure diabetes and protect against its debilitating complications. Substantial obstacles in the field of islet transplantation slowed its clinical implementation for decades. The recent breakthrough with the first series of successful islet transplantation in Edmonton Canada reestablished transplantation of islets of Langerhans as a viable therapeutic option for the cure of type I diabetes. The clinical applicability and wide spread use of this therapy is hampered by two major obstacles:(i) the requirement for a high number of islets derived from at least two pancreata to achieve euglycemia, and (ii) the need for intensive immunosuppression that cannot be given to the pediatric population. The causes underlying the failure of islet transplantation are multifactorial including (i) primary non-function, (ii) allograft rejection and (iii) recurrence of autoimmunity. Regardless of the cause, islets are ultimately destroyed by apoptosis. Efforts directed at engineering "death-defying" islets able to resist immune and non-immune injuries may offer a solution by reducing the number of islets required and allowing the use of milder immunosuppression. Our work is focused on defining "protective" candidates for the genetic engineering of islets. Our preliminary data reveals that A20 is part of the physiological response of islets to injury. Expression of A20 in islets protects from cytokine and Fas/FasL mediated apoptosis and exerts a potent anti-inflammatory effect via blockade of NF-?B. We have already shown that overexpression of A20 in islets overcomes the first hurdle facing successful transplantation namely, primary non-function. We aim to determine whether genetic engineering with the cytoprotective gene A20, will protect islets from allograft rejection (C57BL/6 to diabetic BALB/c) and recurrent autoimmunity (NOD-scid to diabetic NOD). Finally, we will determine whether A20 will enable successful transplantation of allogeneic islets into autoimmune recipients (C57BL/6 into diabetic NOD). Gene transfer will be performed using both recombinant adenoviruses (rAd.) and recombinant associated adenoviruses (rAAV) that have both been shown to efficiently transduce islets without major toxicity or impairment of function. It is our belief that overexpression of the cytoprotective gene A20 will protect islets from the allo and autoimmune insults. This will overcome the requirement for high numbers of islets and the need for intensive immunosuppression. Beneficial results would pave the way for pre-clinical (primates) and clinical applications.

描述（由申请人提供）：胰岛细胞移植治疗I型自身免疫性糖尿病患者具有治愈糖尿病和防止其衰弱性并发症的潜力。几十年来，胰岛移植领域的实质性障碍阻碍了其临床实施。最近在加拿大埃德蒙顿的第一批成功胰岛移植的突破重新确立了朗格汉斯胰岛移植作为治疗I型糖尿病的可行治疗选择。该疗法的临床适用性和广泛使用受到两个主要障碍的阻碍：(i)需要来自至少两个胰腺的大量胰岛来实现血糖正常，（ii）需要强化免疫抑制，而儿童人群无法给予。