Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy.

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils.

Post-translational modification of amyloid a protein in patients with AA amyloidosis.

AA amyloidosis is a disease caused by extracellular deposition of insoluble β-pleated sheet fibrils composed of amyloid A (AA) protein, an amino (N)-terminal fragment of serum amyloid A (SAA). The deposits disrupt tissue structure and compromise organ function. Although the disease is systemic, deposition in kidney glomeruli is the most common manifestation.

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data.

Aims: Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-L (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment.

Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.

The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques.

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis.

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo.

Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy.

Inotersen therapy of transthyretin amyloid cardiomyopathy.

Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy.

Amyloidosis: diagnosis and new therapies for a misunderstood and misdiagnosed disease.

Amyloidosis is a group of diseases characterized by extracellular deposition of amyloid fibril complexes. Fibril deposition results in organ dysfunction and possible failure. Amyloidosis is regarded as a rare disease, but in general is underdiagnosed.

A transgenic mouse model reproduces human hereditary systemic amyloidosis.

Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein.

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of studies, these fragments have been proposed to play important roles in amyloid formation.

A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils.

The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation.

Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.

The nomenclature committee of the International Society of Amyloidosis (ISA) meets every second year to discuss and formulate recommendations. The conclusions from the discussion at the XVI International Symposium on Amyloidosis in Kumamoto, Japan, 25-29 March 2018 and afterwards are summarized in this Nomenclature Article. From having recommended the use of the designation "amyloid fibril" for in vivo material only, ISA's nomenclature committee now accepts its use more broadly following the international scientific literature.

Inotersen (transthyretin-specific antisense oligonucleotide) for treatment of transthyretin amyloidosis.

Hereditary  transthyretin amyloidosis (ATTR) is a fatal systemic disease that results from deposition of the misfolded protein transthyretin (TTR) in tissues. Common clinical manifestations of ATTR include peripheral neuropathy, cardiomyopathy, autonomic dysfunction, diarrhea and constipation. Historically there have not been effective therapies for this devastating disease.

Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial.

Background: Hereditary transthyretin (ATTRm) amyloidosis is a rare, progressive and fatal disease with a range of clinical manifestations.

Objective: This study comprehensively evaluates disease characteristics in a large, diverse cohort of patients with ATTRm amyloidosis.

Methods: Adult patients (N = 172) with Stage 1 or Stage 2 ATTRm amyloidosis who had polyneuropathy were screened and enrolled across 24 investigative sites and 10 countries in the NEURO-TTR trial ( www.

Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition.

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant gene with the wild-type gene.

Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy.

Objectives: Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTR)). Clinically disease progression from time of diagnosis to death is usually quoted as 5- to 15-years. In prior studies, significant progression of cardiac parameters in patients with moderate to severe cardiomyopathy has been noted within a 12-month time span.