title: CSP-1103 (CHF5074) stabilizes human transthyretin in healthy human subjects.
abstract: Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity. In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site. We have previously shown that serum TTR levels were increased by oral CSP-1103 administration through stabilization of TTR tetramers in humanized mice at both the Ttr locus and the Rbp4 locus. To determine whether CSP-1103 stabilizes TTR tetramers in humans, multiple CSP-1103 oral doses were administered for two weeks to 48 healthy human volunteers in a double-blind, placebo-controlled, parallel-group study. CSP-1103 treatment stabilized TTR tetramers in a dose-dependent manner under normal or denaturing stress conditions, thereby increasing serum TTR levels. Preincubation of serum with CSP-1103 or diflunisal in vitro increased the TTR tetramer stability. Computer simulation analysis revealed that the binding affinities of CSP-1103 with TTR at pH 7.0 were similar to those of tafamidis, thus confirming that CSP-1103 has potent TTR-stabilizing activity.
authors.affiliation: a Division of Respiratory Disease , The Fourth Affiliated Hospital of Harbin Medical University , Harbin , China.|b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.
authors.forename: Lixia
authors.initials: L
authors.lastname: Qiang
authors.affiliation: a Division of Respiratory Disease , The Fourth Affiliated Hospital of Harbin Medical University , Harbin , China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Guan
authors.affiliation: a Division of Respiratory Disease , The Fourth Affiliated Hospital of Harbin Medical University , Harbin , China.|b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.
authors.forename: Xiangshun
authors.initials: X
authors.lastname: Li
authors.affiliation: b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.|c Department of Histology and Embryology , Harbin Medical University , Harbin , Heilongjiang , China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.
authors.forename: Yanshuang
authors.initials: Y
authors.lastname: Mu
authors.affiliation: d Division of Medical Informatics and Bioinformatics , Kobe University Hospital , Kobe , Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Sugano
authors.affiliation: d Division of Medical Informatics and Bioinformatics , Kobe University Hospital , Kobe , Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
authors.affiliation: e Department of Pharmacokinetics , Kyoto Pharmaceutical University , Kyoto , Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.affiliation: f Research and Development , Chiesi Farmaceutici , Parma , Italy.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.affiliation: b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Yamamura
authors.affiliation: a Division of Respiratory Disease , The Fourth Affiliated Hospital of Harbin Medical University , Harbin , China.
authors.forename: Shoude
authors.initials: S
authors.lastname: Jin
authors.affiliation: c Department of Histology and Embryology , Harbin Medical University , Harbin , Heilongjiang , China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Li
mesh_terms: D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D003521:Cyclopropanes / Q000627:therapeutic use; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000627:therapeutic use; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D011228:Prealbumin; D005480:Flurbiprofen; D013974:Thyroxine
keywords: Amyloidosis; genetic disease; stabilization; treatment