title: Induced pluripotent stem cell modeling of multisystemic, hereditary transthyretin amyloidosis.
abstract: Familial transthyretin amyloidosis (ATTR) is an autosomal-dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR, protein secreted from the liver aggregates and forms fibrils in target organs, chiefly the heart and peripheral nervous system, highlighting the need for a model capable of recapitulating the multisystem complexity of this clinically variable disease. Here, we describe the directed differentiation of ATTR patient-specific iPSCs into hepatocytes that produce mutant TTR, and the cardiomyocytes and neurons normally targeted in the disease. We demonstrate that iPSC-derived neuronal and cardiac cells display oxidative stress and an increased level of cell death when exposed to mutant TTR produced by the patient-matched iPSC-derived hepatocytes, recapitulating essential aspects of the disease in vitro. Furthermore, small molecule stabilizers of TTR show efficacy in this model, validating this iPSC-based, patient-specific in vitro system as a platform for testing therapeutic strategies.
authors.affiliation: Sections of Hematology-Oncology and Computational Biomedicine, Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA ; Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Leung
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Nah
authors.forename: Whitney
authors.initials: W
authors.lastname: Reid
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ebata
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Koch
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connors
authors.forename: John L
authors.initials: JL
authors.lastname: Berk
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mostoslavsky
authors.forename: Darrell N
authors.initials: DN
authors.lastname: Kotton
authors.forename: George J
authors.initials: GJ
authors.lastname: Murphy
mesh_terms: D000328:Adult; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism
chemical_list: D011228:Prealbumin