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New therapeutic approaches for familial amyloidotic polyneuropathy based on the amyloid formation mechanism

基于淀粉样蛋白形成机制的家族性淀粉样多发性神经病的新治疗方法

基本信息

批准号：
17390254
负责人：
ANDO Yukio
金额：
$ 10.42万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390254/
关键词：
FAP Amyloidosis Transthvretin Gene Therapy Antibody Treatment Trace Element Amyloid Liver Transplantation

项目摘要

From April, 2005 to March, 2008, we performed the following therapeutic experiments for familial amyloidotic polyneuropathy, such as 1.Cr^<3+> therapy to stabilize TTR in tetrameric form, 2.inhibition of amyloid formation by BSB or FSB, 3.antibody therapy targeting for the misfolding epitope which newly expose to the outside of the TTR molecule, and 4.gene therapy using single stranded oligonucleotides(SSOs)to shut out TTR production in the liver and retina. Experimental results were the followings. 1. Administration of Cr^<3+> to the transgenic mice and rats having human ATTR V30M gene did not suppress neither amyloid nor TTR deposition. 2.We prepared amyloid scintigraphy system to detect amyloid deposition in the tissues with real time and also prepared PET system in vivo. 3.Concerning antibody therapy, we focused TTR115-124 fragment antibody to prevent amyloid formation. This epitope reacts with only amyloid fibrils, but not serum TTR. The antibody for TTR115-124 fragment suppressed TTR amyloid formation without reducing serum TTR concentrations in transgenic rat having ATTR V30M gene. 4. SSOs did convert TTR gene in the liver and retina (8% and 1%, respectively). In addition, as an treatment for the ocular amyloidosis occurring even after liver transplantation, we performed laser beam administration to the retinal pigmental cells to reduce the number of the cells, which was promising for retarding the progression of FAP.From these results, we concluded both antibody therapy and gene therapy are promising therapy as an essential therapy for FAP. In the next project, we will focus on these two research projects.

从2005年4月到2008年3月，我们针对家族性淀粉样多发性神经病进行了以下治疗实验，例如1.Cr^3+治疗以稳定四聚体形式的TTR，2.BSB或FSB抑制淀粉样蛋白形成，3.针对新暴露于TTR分子外部的错误折叠表位的抗体治疗，以及 4.使用单链寡核苷酸（SSO）的基因疗法来阻止肝脏和视网膜中TTR的产生。实验结果如下。 1.向具有人ATTR V30M基因的转基因小鼠和大鼠施用Cr 3+ 既不抑制淀粉样蛋白也不抑制TTR沉积。 2.我们制备了淀粉样蛋白闪烁显像系统来实时检测组织中淀粉样蛋白的沉积，并制备了体内PET系统。 3.抗体治疗方面，我们重点关注TTR115-124片段抗体，以防止淀粉样蛋白形成。该表位仅与淀粉样原纤维发生反应，但不与血清 TTR 发生反应。 TTR115-124片段的抗体抑制了具有ATTR V30M基因的转基因大鼠中的TTR淀粉样蛋白形成，而不降低血清TTR浓度。 4. SSO 确实转换了肝脏和视网膜中的 TTR 基因（分别为 8% 和 1%）。此外，作为肝移植后发生的眼部淀粉样变性的治疗方法，我们对视网膜色素细胞进行激光束照射以减少细胞数量，这有望延缓FAP的进展。从这些结果中，我们得出结论，抗体疗法和基因疗法都是有希望作为FAP基本疗法的疗法。在下一个项目中，我们将重点关注这两个研究项目。