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

从2005年4月至2008年3月，我们对家族性淀粉样多发性神经病进行了以下治疗实验，如1. Cr ^<3 +>治疗以稳定TTR四聚体形式，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，和4.使用单链寡核苷酸（SSO）的基因治疗以阻断肝脏和视网膜中TTR的产生。实验结果如下。1.对携带人ATTR V30 M基因的转基因小鼠和大鼠给予Cr ^<3 +>，既不能抑制淀粉样蛋白的沉积，也不能抑制TTR的沉积。2.制备了淀粉样蛋白成像系统，用于真实的实时检测组织中淀粉样蛋白的沉积，并制备了PET系统。3.在抗体治疗方面，我们关注TTR 115 - 124片段抗体以防止淀粉样蛋白形成。该表位仅与淀粉样纤维反应，而不与血清TTR反应。TTR 115 - 124片段的抗体抑制TTR淀粉样蛋白形成，而不降低具有ATTR V30M基因的转基因大鼠中的血清TTR浓度。4. SSO确实在肝脏和视网膜中转化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了激光照射，减少了色素细胞的数量，这对延缓FAP的进展是有希望的。从这些结果中，我们得出结论，抗体治疗和基因治疗作为FAP的基本治疗方法都是有希望的。在下一个项目中，我们将重点关注这两个研究项目。

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.