Stabilization of Cardiac Function With Diflunisal in Transthyretin (ATTR) Cardiac Amyloidosis
Graham LohrmannAlexandra PipilasRoberta MussinelliDeepa M. GopalJohn L. BerkLawreen H. ConnorsNirupama VellankiJennifer HellawellOmar K. SiddiqiJonathan C. FoxMatthew J. MaurerFrederick L. Ruberg
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This chapter contains sections titled: Introduction to Transthyretin Structure and Function Introduction to Amyloid Diseases in General Mechanism of Transthyretin Amyloidogenesis Kinetic Stabilization of the Transthyretin Tetramer through Small-Molecule Binding Assessment of Diflunisal for Treatment of Transthyretin Amyloidosis Tafamidis, the First Approved Drug for Treatment of a Transthyretin Amyloidosis Summary References
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The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition
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"Diflunisal compassive use in transthyretin hereditary amyloid polyneuropathy: report of a first Spanish experience." Amyloid, 24(sup1), pp. 105–106
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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.
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Background Diflunisal is a well known FDA-registered commonly used NSAID therapy in the USA since the 1970’s. In Europe, the drug has been seldom authorised on a national basis with the next safety update report scheduled for 2025 (http://www.ema.europa.eu/ema/). Spain is one such country where commercial use has not been authorised, likely because of concerns on liver hypersensitivity and availability of other NSAIDs. Interestingly, recent advances have shown a potential beneficial effect in transthyretin (TTR) hereditary amyloidosis, as evidenced by encouraging data from the diflunisal trial consortium (Berk et al. JAMA. 2013;310(24):2658-2667) where quality of life, neuropathy impairment scores and nutritional status showed significant, though modest, better results in patients randomised to receive diflunisal instead of placebo.
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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.
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