Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis

Tojo, Koji; Sekijima, Yoshiki; Kelly, Jeffery W.; Ikeda, Shu‐ichi

doi:10.1016/j.neures.2006.08.014

Cited by 139 publications

(103 citation statements)

References 54 publications

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“…Heavy deposition of amyloid was seen in aspirated abdominal fat tissues, and the presence of ATTR Val30Met was confirmed by MALDI/TOF MS analysis of his serum [8]. He is now participating in our clinical trial of diflunisal [10].…”

Section: Case Report Casementioning

confidence: 91%

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy

Tojo

Tsuchiya‐Suzuki

Sekijima

et al. 2010

Amyloid

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We report here two patients with ATTR Val30Met FAP who developed numbness in both hands and were diagnosed as having bilateral carpal tunnel syndrome (CTS). In both patients systemic TTR amyoloidosis consisting of polyneuropathy affecting both upper and lower limbs and/or autonomic dysfunction gradually appeared after surgery for CTS. Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30Met FAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms. It is also notable that both patients had no genealogical relationship with two Japanese endemic foci of this disease.

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Section: Case Report Casementioning

confidence: 91%

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy

Tojo

Tsuchiya‐Suzuki

Sekijima

et al. 2010

Amyloid

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“…3 C and D). By using this previously described technique (23,26,34), we detected the TTR tetramer (Fig. 3C, arrowhead) as well as tetrameric TTR bound to RBP (Fig.…”

Section: Ag10 Increases Stability Of Wt-ttr In Human Serum Against Acid-mentioning

confidence: 98%

“…We next tested AG10 and tafamidis for their ability to stabilize WT-TTR in human serum (Fig. 3 C and D) (26,34). AG10 and tafamidis (concentration range between 0.1 and 10 μM) were preincubated with human serum (TTR ∼5 μM), and the pH was lowered to pH 4.0 to induce dissociation of TTR tetramers.…”

Section: Ag10 Increases Stability Of Wt-ttr In Human Serum Against Acid-mentioning

confidence: 99%

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

Penchala

Connelly

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I-and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy. drug design | crystal structure

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“…The non-steroidal anti-inflammatory drug Diflunisal has been found to have this effect [99], [100] but chronic use is limited due to possible worsening of fluid overload and renal function. Tafamidis is a novel transthyretin kinetic stabilizer which has been recently investigated clinically [101].…”

Section: Disease Specific Treatmentmentioning

confidence: 99%

Treatment of End Stage Heart Failure Related to Cardiac Amyloidosis

Hasin¹,

Raichlin²,

Dispenzieri³

et al. 2013

Amyloidosis

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Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis

Cited by 139 publications

References 54 publications

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

Treatment of End Stage Heart Failure Related to Cardiac Amyloidosis

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