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Tissue remodeling after RNAi-mediated knockdown of TTR in a Familial Amyloidotic Polyneuropathy mouse model


Transthyretin (TTR) deposition in the peripheral nervous system (PNS) is the hallmark of Familial Amyloidotic Polyneuropathy (FAP). Mice expressing human TTR with the V30M mutation in a heterozygous heat shock factor 1 (Hsf-1) background show extensive TTR deposits in PNS and gastrointestinal tract, as well as extracellular matrix (ECM) remodeling, similar to those seen in human FAP patients. Currently, liver transplantation is the only available treatment to halt the progression of clinical symptoms in FAP. Due to the limitations of this procedure, it is of utmost importance to develop alternative therapeutic strategies. In this regard, an RNAi therapeutic targeting TTR for the treatment of FAP is currently in Phase 3 clinical development. An ongoing phase 2 clinical trial in FAP patients demonstrated promising results as a mean plasma TTR reduction of 80%, sustained for over nine months, led to a decrease in neuropathy progression compared to historical data.


To dissect molecular changes occurring in tissues upon RNAi-mediated knockdown of TTR, we treated both chronically and acutely the Hsf/V30M FAP mouse model, in different stages of TTR deposition and analyzed histopathological and biochemical changes in the most affected organs.


Our data show that inhibition of TTR expression by the liver prevent and reverse TTR deposition in PNS and GI tract. In addition, this treatment resulted in ECM remodeling with decreased levels of matrix metalloproteinase-2 (MMP-2) expression and MMP-9 activity in dorsal root ganglia. Importantly, MMP-2 protein levels were found down regulated in plasma samples from older mice treated with RNAi while animals treated with Tafamidis, Anakinra or Doxycycline/TUDCA showed no difference, suggesting that ECM remodeling with decreased MMP-2 might be a specific effect of RNAi.


Collectively, our data show that silencing TTR liver synthesis in vivo can modulate TTR-induced pathology in the PNS.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Gonçalves, N.P., Gonçalves, P., Ventosa, M. et al. Tissue remodeling after RNAi-mediated knockdown of TTR in a Familial Amyloidotic Polyneuropathy mouse model. Orphanet J Rare Dis 10 (Suppl 1), P5 (2015).

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