Gene therapy for progressive renal diseases

进行性肾病的基因治疗

• 批准号: 10470217
• 负责人: IMAI Enyu
• 金额: $ 8.45万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470217/
• 关键词: TGF-β; antisense; gene therapy; HVJ-liposome; interstitial fibrosis; HVJリポソーム法; 糖尿病性腎症; 糸球体肥大; 糸球体基底膜肥厚; 進行性腎障害

There is little doubt that molecular biological intervention therapy has come of age and tremendous excitements have emerged from its potential. A gene transfer technique, HVJ-liposome method is now applicable to the analysis of molecular aspects in pathophysiology of renal diseases, and further to a tool for gene therapy. We demonstrated that continuous delivery of chimeric soluble TGF-β receptor from the gene transferred skeletal muscle also inhibits the extracellular matrix expansion in experimental glomerulonephritis. Furthermore, we challenged whether in vivo gene transfer of antisense ODNs for TGF-β into interstitial fibroblasts can suppress the progression of interstitial fibrosis in unilateral ureteral obstruction model rats. Introduction of TGF-β1 antisense ODNs significantly reduced levels of TGF-β1 and types I collagen mRNA expression in obstructed kidneys, and consequently prevented the extent of interstitial fibrosis following ureteral obstruction. Taken together with clinical observation that up-regulation of TGF-β plays an important role in the formation of various kidney fibrosis, the manipulation of the overexpression of TGF-β may provide a novel way of therapeutic intervention to ameliorate the progression of the renal diseases.

毫无疑问，分子生物学干预疗法已经成熟，其潜力已经产生了巨大的兴奋。HVJ-脂质体法是一种基因转移技术，现已应用于肾脏疾病病理生理学的分子方面的分析，并进一步成为基因治疗的工具。我们证明了从基因转移的骨骼肌连续递送嵌合可溶性TGF-β受体也抑制实验性肾小球肾炎中的细胞外基质扩增。此外，我们还探讨了TGF-β反义寡核苷酸基因转染间质成纤维细胞是否能抑制单侧输尿管梗阻模型大鼠间质纤维化的进展。TGF-β1反义ODNs的导入显著降低了梗阻肾组织TGF-β1和I型胶原mRNA的表达水平，从而阻止了输尿管梗阻后肾间质纤维化的程度。结合TGF-β的上调在各种肾脏纤维化形成中起重要作用的临床观察，操纵TGF-β的过表达可能为改善肾脏疾病的进展提供新的治疗干预途径。

项目成果

Isaka Y, et al: "Prolonged Transgene Expression in Glomeruli Using and Epstein-Barr Virus Replicon Vector System Combined with AVE Type HVJ Liposomes."Kidney Int.. (in press).

Isaka Y 等人：“使用 Epstein-Barr 病毒复制子载体系统与 AVE 型 HVJ 脂质体相结合，延长肾小球中的转基因表达。”Kidney Int..（出版中）。

Enyu Imai and Yoshitaka Isaka: "Strategies of gene transfer to the kidney" Kidney Int. 53. 264-272 (1998)

Enyu Imai 和 Yoshitaka Isaka：“基因转移到肾脏的策略” Kidney Int。

Isaka Y, Tsujie M, Ando Y, Nakamura H, Kanada Y, Imai E, Horio M: "Transforming growth factor-β1 antisense oligodeoxynucleotides block intersutitial fibrosis in unilateral ureteral obstruction"Kidney Int. 58. 1885-1892 (2000)

Isaka Y、Tsujie M、Ando Y、Nakamura H、Kanada Y、Imai E、Horio M：“转化生长因子-β1 反义寡脱氧核苷酸可阻断单侧输尿管梗阻中的间质纤维化”Kidney Int。

Nakamura H,Isaka Y,et al.: "Electroporation-Mediated PDGF Receptor-IgG Chimera Gene Transfer Ameliorated Experimental Glomerulonephritis"Kidney Int.. (2001)

Nakamura H、Isaka Y 等：“电穿孔介导的 PDGF 受体-IgG 嵌合基因转移改善实验性肾小球肾炎”Kidney Int.. (2001)

Nakamura H, Isaka Y, Tsujie M, Akagi Y, Sudo T, Ohno N, Imai E, Hori M: "Electroporation-Mediated PDGF Receptor-IgG Chimera Gene Transfer Ameliorated Experimental Glomerulonephritis."Kidney Int. (in press). (2001)

Nakamura H、Isaka Y、Tsujie M、Akagi Y、Sudo T、Ohno N、Imai E、Hori M：“电穿孔介导的 PDGF 受体-IgG 嵌合体基因转移改善实验性肾小球肾炎。”Kidney Int。