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

Background 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.