Amyloid-Journal of Protein Folding Disorders最新文献

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: Wild-type transthyretin cardiac amyloidosis (ATTRwt) is an infiltrative disease leading to restrictive cardiomyopathy. We aimed to characterise exercise capacity in ATTRwt and to identify predictors of cardiopulmonary fitness, focusing on echocardiographic and clinical parameters.

Methods: We studied 110 ATTRwt patients from a prospective single-centre registry (2020-2024) by cardiopulmonary exercise testing (CPET). Besides CPET, all patients underwent comprehensive clinical assessment including follow-up for mortality. In 32 patients follow-up CPET after 1 year was available.

Results: In ATTRwt, reduced aerobic capacity (pVO2 16 [13-18] ml/kg/min), and ventilatory inefficiency (VE/VCO2 slope 35 [30-43]) were common. In the multivariable regression analysis, we identified TAPSE/sPAP ratio as predictive for pVO2 (p = 0.019) and ventilatory efficiency (p = 0.004), while left ventricular ejection fraction or measures of left ventricular hypertrophy were not predictive. Concordantly, TAPSE/sPAP ratio assessed at baseline predicted pVO2 at 1-year follow-up (p = 0.009). Furthermore, patients with a TAPSE/sPAP ratio below the median of 0.38 mm/mmHg presented a higher risk of all-cause death (p = 0.009).

Conclusion: In ATTRwt the TAPSE/sPAP ratio, a marker of right ventricular coupling, was an independent predictor of aerobic capacity assessed by CPET, at baseline and after 1 year, highlighting the importance of right ventricular assessment for risk stratification.

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.

Background: Light-chain cardiac amyloidosis (AL-CA) is associated with structural and functional changes in the left atrium and left ventricle. This study aims to assess the value of the left atrioventricular coupling index (LACI) assessed by three-dimensional echocardiography (3DE) for predicting primary outcome in AL-CA.

Methods: Participants with biopsy-confirmed AL-CA from April 2022 to February 2024 were prospectively analysed. LACI, the ratio of left atrial volume min to left ventricular end-diastolic volumes, was calculated offline using EchoPAC 204. The primary outcome was defined as all-cause death.

Results: Sixty-seven biopsy-proven AL-CA patients were studied (age: 62.98 ± 10.20 years; 67% male). The median follow-up was 121 days (range: 7 ∼ 732 days). All-cause mortality occurred in 26 (39%) patients. Multivariate Cox regression revealed a significant association of LACI after adjusting for NT-pro BNP, troponin T, moderate tricuspid regurgitation, pericardial and pleural effusion (adjusted HR: 10.58, p = 0.008). Kaplan-Meier curves displayed prognostic differences based on median LACI (cut-off : 0.57, p = 0.002). The likelihood ratio χ2 test showed that LACI added predictive value to Mayo 2004, European 2015 modification of Mayo 2004, and Mayo 2012 models (All p < 0.001).

Conclusions: 3DE-based LACI is independently associated with all-cause mortality in AL-CA patients and augments prognostic value to traditional staging models.

Background: A high incidence of valvular involvement of amyloid in the setting of aortic stenosis (AS) has been reported. Amyloid derived from ApoAI (AApoAI) can form local amyloid deposits in the aortic valve. Although a high prevalence of concomitant severe AS and cardiac transthyretin-type amyloidosis (ATTR) has been reported, the prevalence of valvular involvement by ATTR and AApoAI is unclear.

Methods: Using immunostaining and mass spectrometry, we analysed amyloid proteins in 97 aortic valves removed for valve replacement due to AS at Kyoto Prefectural University of Medicine between 2014 and 2021. Clinical information was also reviewed.

Results: Amyloid deposits were found in 44 cases (45%), of which 30 cases (68%) involved ATTR and 33 cases (75%) AApoAI. Statistical analysis showed significantly lower age and E/e' among amyloid-positive cases compared with amyloid-negative cases and significantly lower brain natriuretic peptide, higher fractional shortening, and higher left ventricular ejection fraction among ATTR-positive cases compared with ATTR-negative cases. Seven recent patients underwent bone scintigraphy and ATTR cardiomyopathy was observed in only one case.

Conclusions: AS symptoms can manifest earlier in patients with amyloid or ATTR deposition in the aortic valve than in patients without such deposition, even though left ventricular function is preserved.