Amyloid-Journal of Protein Folding Disorders最新文献

Background: Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.

Objectives: To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.

Methods: We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies.

Results: Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels.

Conclusions: This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.

AA amyloidosis is a prototypic example of systemic amyloidosis: it results from the prolonged overproduction of SAA protein produced in response to chronic inflammation. AA amyloidosis primarily affects the kidneys, liver, spleen, gastrointestinal tract, leading to a variety of symptoms. First, this review examines AA amyloidosis in humans, focusing on pathogenesis, clinical presentation, and diagnosis and then in animals. In fact AA amyloidosis is the only systemic amyloidosis that has been largely documented in a remarkable number of vertebrate species: mammals, birds, and fishes, especially in individuals with comorbidities, chronic stress, or held in captivity. Secondly, here, we summarise independent sets of evidence obtained on different animal species, exploring the possible transmissibility of AA amyloidosis especially in crowded or confined populations. Finally, biochemical and structural data on native SAA and on AA amyloid fibrils from human, murine, and cat ex vivo samples are discussed. The available structural data depict a complex scenario, where SAA can misfold forming highly different amyloid assemblies. This review highlights the complexity of AA amyloidosis, emphasising the need for further research into its spread in the animal kingdom, its structural aspects, and pathogenetic mechanisms to evaluate its impact on human and animal health.

Background: The investigational monoclonal antibody PRX004 is designed to specifically target and deplete TTR amyloid. Here, we report on the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of PRX004 in patients with ATTRv amyloidosis.

Methods: This global, multicentre, phase 1 trial comprised a 3 + 3 dose-escalation phase and a long-term extension (LTE) phase (NCT03336580). In the dose-escalation phase, patients received PRX004 (0.1, 0.3, 1, 3, 10 or 30 mg/kg), administered intravenously every 28 days for 3 months. In the LTE, eligible patients could receive up to 15 additional doses. Patients who received doses of ≥3 mg/kg for ≥9 months were assessed for Global Longitudinal Strain (GLS) and Neuropathy Impairment Score (NIS). The primary objective was to determine the maximum tolerated dose (MTD) of PRX004.

Results: Overall, 21 patients with ATTRv amyloidosis completed the dose-escalation phase; 17 subsequently enrolled in the LTE. The MTD was not reached. PRX004 was well tolerated at all doses, with dose-proportional exposure. GLS and NIS were improved or maintained over 9 months (n = 7).

Conclusions: PRX004 was well tolerated in patients with ATTRv amyloidosis and demonstrated potential clinical activity. A phase 2 randomised controlled trial in ATTR cardiomyopathy is ongoing (NCT05442047).

Background: The NEURO-TTRansform trial showed that after 66 weeks of treatment, eplontersen significantly reduced neuropathic impairment and improved quality of life (QoL) in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). In this secondary analysis from NEURO-TTRansform, autonomic impairment, and the impact of eplontersen on autonomic impairment progression was evaluated through 85 weeks in patients randomised to eplontersen (n = 144) versus external placebo (n = 60; through Week 66 from the NEURO-TTR trial).

Methods: Change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, and the Neuropathy Symptoms and Change (NSC) total score was evaluated. Exploratory assessments were change in autonomic components of these instruments, Composite Autonomic Symptom Score-31 (COMPASS-31) total score, and nutritional status (modified body mass index [mBMI]).

Results: Patients reported profound autonomic dysfunction at baseline. Improvements with eplontersen versus placebo were observed up to Week 66 in autonomic components of mNIS+7, Norfolk QoL-DN, NSC, and mBMI; eplontersen results were sustained up to Week 85, including improvements in COMPASS-31 (Week 81).

Conclusions: Eplontersen demonstrated benefit across multiple measures of autonomic impairment known to progress rapidly and negatively impact QoL without treatment, without deterioration in nutritional status.

Background: Proteomics is routinely used to type clinical amyloid deposits, and offers additional benefit of identifying genetic variants, which can be diagnostically useful. Reviewing the proteomics data for ATTR patients attending our Centre revealed an unusually large number of samples containing a rare pathogenic H90D TTR variant alongside the more common H90N variant.

Methods: These findings raised questions to their source. Proteomics was used to monitor the generation of H90D/H90N variants in fresh, frozen, stored samples during extraction and digestion, and also following Cu²⁺-mediated oxidation.

Results: There was no evidence that the variants were present in the circulation, except in one patient with genetically confirmed H90D TTR, in fresh fat aspirates or tissues from an ATTR amyloid mouse model. The variant could be generated in vitro from both wild-type TTR and ex vivo ATTR fibrils by non-enzymic oxidation of histidine at position 90. These data suggest that the H90D variant can be generated artefactually from wild-type 90H TTR through a radical-mediated oxidation of histidine, followed by its conversion to asparagine and aspartic acid. This probably occurs during storage.

Conclusions: In the absence of genetic data, the identification of H90D TTR in stored tissue by proteomics should be treated with caution.

Background: Diarrhoea is one of the most serious complications in hereditary ATTR (ATTRv) amyloidosis. However, its precise pathomechanism remains unknown. The present study investigated the involvement of bile acid in diarrhoea along with the therapeutic effect of colestimide, a bile acid sequestrant, in ATTRv amyloidosis.

Methods: We prospectively enrolled 19 ATTRv amyloidosis patients (9 with refractory diarrhoea and 10 without diarrhoea) and 20 healthy individuals for measurements of serum 7a-hydroxy-4-cholesten-3-one (C4) levels. The patients with diarrhoea were then treated with oral colestimide (1.5 g twice daily) for 28 days. The frequency of diarrhoea and C4 level were evaluated before and after colestimide treatment.

Results: Mean serum C4 level was significantly higher in ATTRv patients with diarrhoea (62.3 ng/mL) than in ATTRv patients without diarrhoea (24.0 ng/mL, p = 0.03). Colestimide treatment significantly decreased mean diarrhoea frequency (pre-treatment period: 9.1 times/week, colestimide treatment period, 6.6 times/week, p = 0.04) and increased mean C4 level (before treatment: 66.2 ng/mL, after treatment: 187.1 ng/mL, p = 0.02).

Conclusions: Bile acid status was significantly associated with diarrhoea in ATTRv amyloidosis. Colestimide and other bile acid sequestrants may reduce diarrhoea frequency in afflicted patients.