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Gene-engineered dendritic cell therapy for diabetics

针对糖尿病患者的基因工程树突状细胞疗法

基本信息

批准号：
7119507
负责人：
MASSIMO M. TRUCCO
金额：
$ 54.68万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2010-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes mellitus is an autoimmune disease whose etiopathogenesis lies in the selective destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The current insulin replacement therapy strategies are not fully effective at recapitulating tight glucose control. While transplantation of intact islets of Langerhans offers the potential to restore physiologic glycemic control, the requirement for life-long immunosuppressive interventions carries with it significant risks of rendering the islet transplants dysfunctional. However, these strategies can lead to an array of other problems including kidney failure and a risk of malignancy. The objective of this collaborative application combining the efforts of the Diabetic Clinic of the Children's Hospital of Pittsburgh, The Diabetes Institute and the Cancer Institute of the University of Pittsburgh is to extend and adapt our initial successful dendritic cell-based approach of prolonging the onset time of diabetes in the NOD mouse. We will inject new-onset diabetic NOD mice with gene engineered DC to manipulate the immune system with the objective of preserving residual beta cell mass that can sustain reduced glycemia or even a return to normoglycemia. Once we confirm this, we propose to initiate a safety trial in new-onset diabetic human volunteers. In this approach, volunteers will be given a single injection of gene-engineered DC and safety will be assessed by different and complementary criteria. The gene-engineered DC will consist of autologous DC propagated ex vivo from peripheral blood mononuclear cells and treated with short, double-stranded oligodeoxyribonucleotide decoys for the transcription factor NF-kB (NF-kB ODN). In a similar approach, antisense oligonucleotides targeted to the CD40, CD80 and CD86 primary transcripts will be used in place of the NF-kB decoys. We divide this application into two sections. The first will deal with studies primarily in the NOD mouse to demonstrate proof-of-principle and will culminate in a application for a limited safety trial in human diabetic volunteers. The second will extend the safety trial into a larger population of diabetics and will culminate in a preliminary examination of the potential of our approach to preserve residual beta cell mass and function as assessed by stimulated C-peptide level and hemoglobin Ale as a surrogate marker. If the results are encouraging, these approaches could be attempted in a larger human population with an objective of lowered insulin requirements, decreased dosage and perhaps a gradual tapering off of insulin. The ultimate result could include less intensive or even a complete cessation of insulin replacement therapy in newly-diagnosed diabetics as well as, perhaps, a means of preventing diabetes.

描述(由申请人提供)： 1型糖尿病是一种自身免疫性疾病，其病因在于选择性地破坏胰腺朗格汉斯胰岛产生胰岛素的β细胞。目前的胰岛素替代治疗策略在总结严格的血糖控制方面并不完全有效。虽然完整的朗格汉斯胰岛移植提供了恢复生理性血糖控制的可能性，但对终身免疫抑制干预的要求伴随着使胰岛移植功能障碍的重大风险。然而，这些策略可能会导致一系列其他问题，包括肾衰竭和恶性肿瘤的风险。这一合作应用程序结合了匹兹堡儿童医院糖尿病诊所、匹兹堡大学糖尿病研究所和匹兹堡大学癌症研究所的努力，目的是扩展和调整我们最初成功的基于树突状细胞的方法，延长NOD小鼠糖尿病的发病时间。我们将向新发病的糖尿病NOD小鼠注射基因工程树突状细胞来操纵免疫系统，目的是保存残留的β细胞群，以维持血糖降低甚至恢复正常血糖。一旦我们确认了这一点，我们建议在新发的糖尿病患者志愿者身上启动一项安全性试验。在这种方法中，志愿者将接受一次基因工程DC的注射，安全性将通过不同和互补的标准进行评估。基因工程DC将由从外周血单个核细胞体外扩增的自体DC组成，并用转录因子NF-kB的短链双链寡核苷酸诱骗(NF-kB ODN)处理。在类似的方法中，针对CD40、CD80和CD86初级转录本的反义寡核苷酸将用来取代核因子-kB诱骗。我们将此应用程序分为两个部分。第一项将主要在NOD小鼠身上进行研究，以证明原理，最终将申请在人类糖尿病志愿者身上进行有限的安全性试验。第二项试验将把安全性试验扩展到更多的糖尿病患者群体，最终将初步检验我们的方法保存剩余β细胞质量和功能的潜力，通过刺激的C肽水平和作为替代标记物的血红蛋白Ale进行评估。如果结果令人鼓舞，这些方法可以在更大的人群中尝试，目标是降低胰岛素需求，减少剂量，或许还可以逐步减少胰岛素的使用。最终结果可能包括减少新诊断糖尿病患者的胰岛素替代治疗强度，甚至完全停止治疗，或许还包括一种预防糖尿病的方法。