CHF5074 (CSP-1103) stabilizes human transthyretin in mice humanized at the transthyretin and retinol-binding protein loci

Familial amyloidotic polyneuropathy is one type of protein misfolding disease. Transthyretin (TTR) tetramer dissociation is the limiting step for amyloid fibril formation. CHF5074 (CSP-1103) stabilizes TTR tetramer in vitro by binding to the T4 binding site. Here, we used three strains of double humanized mice (mTtr^{hTTRVal30/hTTRVal30}, mTtr^{hTTRVal30/hTTRMet30}, and mTtr^{hTTRMet30/hTTRMet30}) to assess whether CHF5074 stabilizes TTR tetramers in vivo. Treatment of mice with CHF5074 increased serum TTR levels by stabilizing TTR tetramers. Although the binding affinities of CHF5074 and diflunisal with TTRMet30 were similar, CHF5074 bound TTRVal30 more strongly than did diflunisal, suggesting the potent TTR-stabilizing activity of CHF5074.