title: TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies.
abstract: BACKGROUND
  Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.
  
  
  METHODS
  We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.
  
  
  CONCLUSIONS
  Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.
authors.affiliation: a Neurology , CHU Bicêtre, APHP , Le Kremlin Bicêtre , France.|b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: a Neurology , CHU Bicêtre, APHP , Le Kremlin Bicêtre , France.|b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Cauquil
authors.affiliation: a Neurology , CHU Bicêtre, APHP , Le Kremlin Bicêtre , France.|b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.
authors.forename: Céline
authors.initials: C
authors.lastname: Labeyrie
authors.affiliation: b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.|d Neurophysiology , CHU Bicêtre, APHP , Le Kremlin Bicêtre , France.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Beaudonnet
authors.affiliation: b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.|e Cardiology , CHU A Beclere, APHP , Clamart , France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Algalarrondo
authors.affiliation: a Neurology , CHU Bicêtre, APHP , Le Kremlin Bicêtre , France.|b National reference Center for FAP (NNERF) , Le Kremlin Bicêtre , France.|c FILNEMUS Filière nationale des maladies neuromusculaires , Marseille , France.
authors.forename: Marie
authors.initials: M
authors.lastname: Théaudin
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy*; D001583:Benzoxazoles / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D004061:Diflunisal / Q000627:therapeutic use*; D018450:Disease Progression; D020868:Gene Silencing; D006801:Humans; D016031:Liver Transplantation; D011228:Prealbumin / Q000378:metabolism*; D017457:Receptors, Albumin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001583:Benzoxazoles; D011228:Prealbumin; D017457:Receptors, Albumin; C091986:transthyretin receptor; D004061:Diflunisal; C547076:tafamidis
keywords: ALN-TTR02 patisiran; ISIS TTR-Rx; Mab GSK2398852; TTR gene silencing; TTR kinetic stabilizer; Transthyretin; diflunisal; familial amyloidotic polyneuropathy; liver transplantation; tafamidis