title: An overview of drugs currently under investigation for the treatment of transthyretin-related hereditary amyloidosis.
abstract: BACKGROUND
  Transthyretin (TTR)-related hereditary amyloidosis is an adult-onset, dominantly inherited, systemic neurodegenerative disease endemic in some populations. Stabilization of the native structure of TTR by small-molecule ligands has recently proved effective in slowing neurological progression. Two drugs, tafamidis and diflunisal, are now available for most patients, particularly in the early stage of the disease. However, this disorder remains life threatening with several unmet needs. There are great expectations for a number of novel agents undergoing investigation.
  
  
  METHODS
  The authors review the current investigational drugs for the treatment of TTR amyloidosis according to the different steps of the fibrillogenesis process they target. Innovative approaches include suppression of TTR secretion, prevention of TTR misfolding by stronger stabilizers identified through structure-based design and high-throughput screening methodologies as well as the redirection of pathogenic aggregates toward nontoxic species and reabsorption of deposits through amyloid disrupters and immunotherapy.
  
  
  CONCLUSIONS
  Suppression of TTR synthesis by antisense oligonucleotides and small-interfering RNA is presently one of the most promising therapeutic approaches. However, well-designed clinical trials are required to establish their safety and efficacy compared with liver transplantation, tafamidis and diflunisal. With a longer time frame, it may be possible to develop combination therapies that target multiple steps of the aggregation process that could provide the best long-life effective treatments for this devastating disease.
authors.affiliation: Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo , Viale Golgi, 19, 27100 Pavia , Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
mesh_terms: D000328:Adult; D017668:Age of Onset; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D015195:Drug Design; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000008:administration & dosage
chemical_list: D015507:Drugs, Investigational; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering
keywords: RNAi; anti-amyloid agents; antisense oligonucleotides; diflunisal; doxycycline; epigallocatechin gallate; kinetics stabilizers; monoclonal antibodies; protein misfolding; tafamidis