Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Koike, Haruki; Katsuno, Masahisa

doi:10.3390/biomedicines7010011

Cited by 60 publications

(101 citation statements)

References 84 publications

(155 reference statements)

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“…26 In contrast, the distortion and atrophy of large Schwann cells, particularly those associated with the large myelinated fibers are not conspicuous even though they appose to the aggregation of amyloid fibrils ( Figure 4). 2 These findings suggest that the predominant loss of small-diameter nerve fibers that distinguish the early-onset ATTR…”

Section: Lesions In the Peripheral Nervous Systemmentioning

confidence: 91%

“…Small Schwann cells, particularly those associated with the unmyelinated fibers, seem to be susceptible to this direct damage by amyloid fibrils . In contrast, the distortion and atrophy of large Schwann cells, particularly those associated with the large myelinated fibers are not conspicuous even though they appose to the aggregation of amyloid fibrils (Figure ) . These findings suggest that the predominant loss of small‐diameter nerve fibers that distinguish the early‐onset ATTR Val30Met amyloidosis patients from conventional endemic foci can be credited to the direct impact of formation of amyloid fibrils on the neighboring tissues …”

Section: Pathological Featuresmentioning

confidence: 99%

“…In 2018, the results of phase III clinical trials of intravenously administrated siRNA, patisiran, and subcutaneously administrated ASO, inotersen, were published . As both studies achieved their primary endpoints, these gene‐silencing drugs seem to be the most optimal treatment for ATTRv amyloidosis if the long‐term efficacy and tolerability are confirmed . Regarding the study of inotersen, thrombocytopenia and glomerulonephritis were reported as serious adverse events …”

Section: Recent Advances In the Treatmentmentioning

confidence: 99%

“…TTR is a transport protein primarily synthesized in the liver, retinal pigment epithelium in the eye, and choroid plexus in the brain . Wild‐type TTR is a stable homotetramer and functions as a thyroxin and retinol (vitamin A)‐binding protein transporter, whereas variant TTR tends to induce dissociation of the TTR tetramer into monomers, causing the deposition of amyloid fibrils in the extracellular spaces . ATTRv amyloidosis was initially reported in Portugal and subsequently in the restricted areas of Japan and Sweden .…”

Section: Introductionmentioning

confidence: 99%

“…1 Wild-type TTR is a stable homotetramer and functions as a thyroxin and retinol (vitamin A)-binding protein transporter, whereas variant TTR tends to induce dissociation of the TTR tetramer into monomers, causing the deposition of amyloid fibrils in the extracellular spaces. 2,3 ATTRv amyloidosis was initially reported in Portugal and subsequently in the restricted areas of Japan and Sweden. 4 Recent advances in the diagnosis and treatment of ATTRv amyloidosis have raised its awareness among physicians even in non-endemic areas, leading to a significant increase in the newly diagnosed patients.…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathological spectrum and recent advances in the treatment of hereditary transthyretin amyloidosis

Koike

Fukami

Nishi

et al. 2019

Neurology & Clinical Neurosc

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Hereditary transthyretin (ATTRv) amyloidosis, also known as familial amyloid polyneuropathy, is a disease caused by the systemic deposition of variant transthyretin (TTR). Although this disease was primarily indigenous to endemic foci in Portugal, Japan, and Sweden, its prevalence has increased throughout the world. The clinical phenotypes of ATTRv amyloidosis are diverse, including neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation type and age of onset. Val30Met, one of the most common TTR mutations, exhibits varying characteristic features in the early‐onset patients from conventional endemic foci and the late‐onset patients from non‐endemic areas. Autonomic dysfunctions and dissociated sensory loss are the characteristic features of the former, whereas motor dysfunctions and loss of all sensory modalities are conspicuous in the latter. Distortion and atrophy of the Schwann cells due to the formation of amyloid fibrils seem to cause predominant small‐fiber loss in the early‐onset patients, while other mechanisms, such as microangiopathy and the toxicity of TTR oligomers, may contribute to nerve fiber loss in the late‐onset patients. In addition to liver transplantation, novel and less invasive disease‐modifying therapies, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotide, have been shown to be effective in ATTRv amyloidosis patients. Given their ability to ameliorate ATTRv amyloidosis, early diagnosis and treatment are required. Physicians should be aware of the diversity in ATTRv amyloidosis because this disease can be misdiagnosed with other diseases such as chronic inflammatory demyelinating polyneuropathy and immunoglobulin light‐chain amyloidosis.

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Section: Lesions In the Peripheral Nervous Systemmentioning

confidence: 91%

Section: Pathological Featuresmentioning

confidence: 99%

Section: Recent Advances In the Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinicopathological spectrum and recent advances in the treatment of hereditary transthyretin amyloidosis

Koike

Fukami

Nishi

et al. 2019

Neurology & Clinical Neurosc

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The Bioequivalence of Tafamidis 61‐mg Free Acid Capsules and Tafamidis Meglumine 4 × 20‐mg Capsules in Healthy Volunteers

Lockwood

O'Gorman

et al. 2020

Clinical Pharm in Drug Dev

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Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

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Expanding the spectrum of transthyretin amyloidosis

Koike

Katsuno

2019

Muscle and Nerve

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Transthyretin (TTR) is one of the proteins that may cause amyloidosis. 1 Although TTR is synthesized mainly in the liver, it is also produced at other sites, such as the choroid plexus in the brain and the retinal pigment epithelium in the eye. 2 Transthyretin produced in the liver is responsible for the major manifestations of amyloidogenic transthyretin (ATTR) amyloidosis, such as neuropathy and cardiomyopathy, whereas TTR produced in the choroid plexus and the retinal pigment epithelium causes oculoleptomeningeal amyloidosis. 1 Amyloidosis caused by TTR deposition (ie, ATTR amyloidosis) is divided into two types: the first occurs in patients without mutation in the TTR gene, and the other occurs in those with a TTR mutation. 2 The former was traditionally known as senile systemic amyloidosis and the latter as familial amyloid polyneuropathy; however, according to recent nomenclature recommendations from the International Society of Amyloidosis, these diseases are designated wild-type ATTR (ATTRwt) amyloidosis and hereditary ATTR (ATTRv; v for variant) amyloidosis, respectively. 3

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Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Cited by 60 publications

References 84 publications

Clinicopathological spectrum and recent advances in the treatment of hereditary transthyretin amyloidosis

Clinicopathological spectrum and recent advances in the treatment of hereditary transthyretin amyloidosis

The Bioequivalence of Tafamidis 61‐mg Free Acid Capsules and Tafamidis Meglumine 4 × 20‐mg Capsules in Healthy Volunteers

Expanding the spectrum of transthyretin amyloidosis

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