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Background: Hereditary amyloidogenic transthyretin (ATTR) amyloidosis is characterized by aggregation of ATTR in various organs. Previously, we reported that polyamidoamine dendrimer (dendrimer) shows inhibitory effects on the formation of ATTR amyloid fibril, and breaking effects on ATTR amyloid fibril in vitro. In addition, we reported that glucuronylglucosyl-b-cyclodextrin/dendrimer conjugate (GUG-b-CDE) exhibits superior gene transfer activity. Objec-tive: In this study, we newly prepared GUG-b-CDE/TTR short hairpin RNA (shTTR) complex, and evaluated the RNAi effect against TTR gene expression, inhibitory effects on the formation of ATTR amyloid fibril, and breaking effects on ATTR amyloid fibril. Materials and Methods: Thioflavin-T (Th-T) assay was performed for the quantitation of ATTR amyloid fibril. Human ATTR transgenic (Tg) rats (9 months) were used as a rats’ model of early onset ATTR V30M amyloidosis, in which ATTR started deposition in colon. In addition, Tg rats (15 months) were used as a rats’ model of late onset AATTR V30M amyloidosis, in which ATTR was already deposited in colon. Both human ATTR Tg rats were treated with GUG-b-CDE/shTTR complex through tail vain injection twice per week during 3 months. ATTR deposition in colon of Tg rats were evaluated by immunostaining. RESULTS: GUG-b-CDE/shTTR complex significantly inhibited ATTR amyloid fibril formation, and drastically dissolved ATTR amyloid fibril. The RNAi effect of GUG-b-CDE/shTTR complex was higher than that of dendrimer/shTTR complex in human hepatocyte HepG2 cells. Moreover, in rats’ models of early and late onset ATTR amyloidosis, intravenous administration of GUG-b-CDE/shTTR complex to ATTR Tg rats significantly suppressed TTR mRNA level in a part of the liver and ATTR depo-sition in colon. CONCLUSION: GUG-b-CDE/shTTR complex may have potential as a novel therapeutic agent for ATTR amyloidosis through the multiple function, such as RNAi effects, inhibitory effects on ATTR amyloid fibril formation, and breaking effects on the ATTR amyloid fibrils.