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

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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.