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.

Keywords:

• Amyloidosis
• stabilization
• genetic disease
• treatment

Disclosure statement

The manuscript has been carefully edited by Nature Research Editing Service (http://authorservices.springernature.com). This study was partly funded by Chiesi Farmaceutici, Parma, Italy. This work was supported by Grants-in-Aid for Scientific Research (C) [24590404 to Z.L.] and (S) [21220010 to K.Y.] from the Japan Society for the Promotion of Science, the Major Program of Natural Science Foundation of Heilongjiang Province of China [ZD2016014 to S.J.], the Dean Foundation and Foster Foundation of the Fourth Hospital of Harbin Medical University (to S.J.), Scientific Support Programs for Cancer Research, a Grant-in-Aid for Scientific Research on Innovative Areas, the Ministry of Education, Culture, Sports, Science and Technology [221S0001 to K.Y.] and CREST (Japan Science and Technology Agency) (to K.Y.).

Additional information

Funding

This study was partly funded by Chiesi Farmaceutici, Parma, Italy. This work was supported by Grants-in-Aid for Scientific Research (C) [24590404 to Z.L.] and (S) [21220010 to K.Y.] from the Japan Society for the Promotion of Science, the National Natural Science Foundation of China [Grant number 81670028 to SJ], the Major Program of Natural Science Foundation of Heilongjiang Province of China [ZD2016014 to S.J.], the Dean Foundation and Foster Foundation of the Fourth Hospital of Harbin Medical University (to S.J.), Scientific Support Programs for Cancer Research, a Grant-in-Aid for Scientific Research on Innovative Areas, the Ministry of Education, Culture, Sports, Science and Technology [221S0001 to K.Y.] and CREST (Japan Science and Technology Agency) (to K.Y.).