Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report

Fujita, Toshio; Inomata, Takayuki; Kaida, Toyoji; Iida, Yasuhiko; Ikeda, Yuki; Nabeta, Takeru; Ishii, Shunsuke; Maekawa, Emi; Naruke, Tsuguo; Koitabashi, Toshimi; Kitamura, Eiji; Sekijima, Yoshiki; Ako, Junya

doi:10.1159/000455089

“…1 and 2) (19,20). Thus our results offer a plausible explanation for the reported limited efficacy of tafamidis over the long term, when administered at late stages, or in patients with severe cardiac involvement (8,21,22). That is, stabilization of tetrameric TTR may be insufficient in situations in which seeded polymerization dominates rather than de-novo nucleation of TTR seeds.…”

Section: Discussionmentioning

confidence: 74%

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Saelices

¹

,

Chung

²

,

Lee

³

et al. 2018

Preprint

View full text Add to dashboard Cite

Amyloid deposition of the hormone transporter transthyretin causes familial and sporadic amyloidoses. The current treatment for familial cases is gene-therapy by liver transplantation. However, this procedure is often insufficient to stop subsequent cardiac deposition. Our recent work has shown that preformed amyloid fibrils present in the heart by the time of surgery can template or seed further polymerization of native transthyretin. No drugs have been approved to stop or slow this seeding process; the only treatment option is heart transplantation. Here we explore two potential inhibitory mechanisms. Of clinical significance, we found that tetramer stabilization does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex-vivo fibrils efficiently inhibits amyloid seeding in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach to be further explored.

show abstract

“…For instance, of clinical importance for ATTR patients with cardiac pathology, liver transplantation sometimes fails to stop disease progression and leads to cardiac wild-type TTR deposition and heart failure (Liepnieks and Benson, 2007). TTR stabilization by tafamidis has been approved for the treatment of only FAP-V30M at an early stage because it has proven to be insufficient to stop disease progression at late stages or in patients with cardiac involvement (Bulawa et al, 2012; Lozeron et al, 2013; Fujita et al, 2017). It is imperative to develop additional therapeutic tools for those cases for which stabilization of TTR or liver transplantation may not be fully effective or not recommended.…”

Section: Resultsmentioning

confidence: 99%

Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Saelices

¹

,

Pokrzywa²,

Pawelek³

et al. 2018

Neurobiology of Disease

View full text Add to dashboard Cite

Transthyretin amyloidosis (ATTR) is a fatal disease caused by the systemic aggregation and deposition of transthyretin (TTR), a blood transporter that is mainly produced in the liver. TTR deposits are made of elongated amyloid fibrils that interfere with normal tissue function leading to organ failure. The current standard care for hereditary neuropathic ATTR is liver transplantation or stabilization of the native form of TTR by tafamidis. In our previous work, we explored an additional strategy to halt protein aggregation by capping pre-existing TTR fibrils with structure-based designed peptide inhibitors. Our best peptide inhibitor TabFH2 has shown to be effective at inhibiting not only TTR aggregation but also amyloid seeding driven by fibrils extracted from ATTR patients. Here we evaluate the effects of peptide inhibitors in two Drosophila models of neuropathic ATTR and compared their efficacy with diflunisal, a protein stabilizer currently used off-label for the treatment of ATTR. Our peptide inhibitor TabFH2 was found the most effective treatment, which resulted in motor improvement and the reduction of TTR deposition. Our in vivo study shows that inhibiting TTR deposition by peptide inhibitors may represent a therapeutic strategy for halting the progression of ATTR.

show abstract

“…For instance, of clinical importance for ATTR patients with cardiac pathology, liver transplantation sometimes fails to stop disease progression and leads to cardiac wild-type TTR deposition and heart failure (Liepnieks and Benson, 2007). TTR stabilization by tafamidis has been approved for the treatment of only FAP-V30M at an early stage because it has proven to be insufficient to stop disease progression at late stages or in patients with cardiac involvement (Bulawa et al, 2012;Lozeron et al, 2013;Fujita et al, 2017). It is imperative to develop additional therapeutic tools for those cases for which stabilization of TTR or liver transplantation may not be fully effective or not recommended.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the effects of transthyretin peptide inhibitors inDrosophilamodels of neuropathic ATTR

Saelices

¹

,

Pokrzywa²,

Pawelek³

et al. 2018

Preprint

1

0

View full text Add to dashboard Cite

Transthyretin amyloidosis (ATTR) is a fatal disease caused by the systemic aggregation and deposition of transthyretin (TTR), a blood transporter that is mainly produced in the liver. TTR deposits are made of elongated amyloid fibrils that interfere with normal tissue function leading to organ failure. The current standard care for hereditary neuropathic ATTR is liver transplantation or stabilization of the native form of TTR by tafamidis. In our previous work, we explored an additional strategy to halt protein aggregation by capping pre-existing TTR fibrils with structure-based designed peptide inhibitors. Our best peptide inhibitor TabFH2 has shown to be effective at inhibiting not only TTR aggregation but also amyloid seeding driven by fibrils extracted from ATTR patients. Here we evaluate the effects of peptide inhibitors in two Drosophila models of neuropathic ATTR and compared their efficacy with diflunisal, a protein stabilizer currently used off-label for the treatment of ATTR. Our peptide inhibitor TabFH2 was found the most effective treatment, which resulted in motor improvement and the reduction of TTR deposition. Our in vivo study shows that inhibiting TTR deposition by peptide inhibitors may represent a therapeutic strategy for halting the progression of ATTR.SIGNIFICANCE STATEMENTFamilial Amyloid Polyneuropathy (FAP) is a hereditary condition caused by the deposition of transthyretin (TTR) in nerves. Marked by progressive deficit and disability, FAP has no cure and limited therapeutic options. The replacement of the production source of mutant TTR by liver transplantation and the stabilization of native TTR by compounds, current lines of treatment, often fail to halt disease progression. Previously, we discovered that two segments of TTR drive amyloid deposition, and designed structure-based peptide inhibitors. Here we evaluate these peptide inhibitors in FAP models of Drosophila. The most efficient inhibitor resulted in an improvement of locomotor abilities and a reduction of TTR deposition. This study points to peptide inhibitors as a potential therapeutic strategy for FAP.

show abstract

Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report

Cited by 7 publications

References 10 publications

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Assessment of the effects of transthyretin peptide inhibitors in Drosophila models of neuropathic ATTR

Assessment of the effects of transthyretin peptide inhibitors inDrosophilamodels of neuropathic ATTR

Contact Info

Product

Resources

About