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A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics.

ABSTRACT: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR amyloidosis, protein secreted from the liver aggregates and forms amyloid fibrils in downstream target organs, chiefly the heart and peripheral nervous system. Few animal models of ATTR amyloidosis exist and none recapitulate the multisystem complexity and clinical variability associated with disease pathogenesis in patients. Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development, model disease, and perhaps treat patients afflicted with highly variable multisystem diseases such as ATTR amyloidosis. Here, we fully characterize six representative iPSC lines from a library of previously reprogrammed iPSC lines and reprogrammable blood samples derived from ATTR amyloidosis patients. This unique resource, described herein, can be harnessed to study diverse disorder.

SUBMITTER: Giadone RM

PROVIDER: S-EPMC6319917 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics.

Giadone Richard M RM Rosarda Jessica D JD Akepati Prithvi Reddy PR Thomas Arianne C AC Boldbaatar Batbold B James Marianne F MF Wilson Andrew A AA Sanchorawala Vaishali V Connors Lawreen H LH Berk John L JL Wiseman R Luke RL Murphy George J GJ

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20180721 3

Hereditary transthyretin amyloidosis (ATTR amyloidosis) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR amyloidosis, protein secreted from the liver aggregates and forms amyloid fibrils in downstream target organs, chiefly the heart and peripheral nervous system. Few animal models of ATTR amyloidosis exist and none recapitulate the multisystem complexity and clinical variability associated with disease pathogenesis ...[more]

PMID: 30032658

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Project description:AimsThe aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA).Methods and resultsA retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs.ConclusionConventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Project description:BackgroundTransthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression.ObjectivesThe goal of this study was to assess the prognostic importance of an increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA.MethodsWe evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677).ResultsBetween baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001).ConclusionsNT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

Project description:IntroductionTransthyretin amyloidosis (ATTR amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene or aggregation of wild-type transthyretin (ATTRwt). In Spain, there are two large endemic foci of ATTR amyloidosis caused by the Val30Met variant, with additional cases across the country; however, these data may be incomplete, as there is no centralized patient registry. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. This analysis aimed to gain a deeper understanding of the clinical profile of patients with ATTR amyloidosis in Spain.MethodsThis was a descriptive analysis of the demographic and clinical characteristics of symptomatic patients enrolled at six sites geographically dispersed throughout Spain (data cutoff: January 6, 2020). Patient data at enrollment, including genotype, demographics, and clinical presentation for symptomatic patients, were recorded. Patients were grouped by predominant phenotype based on clinical measures at enrollment: predominantly cardiac, predominantly neurologic, or mixed (cardiac and neurologic).ResultsThere were 379 patients (58.0% male; 63.3% symptomatic) enrolled in the six THAOS sites in Spain. Predominant genotypes were the Val30Met mutation (69.1%) or ATTRwt (15.6%). Predominant phenotype distribution was neurologic (50.4%), mixed (35.8%), and cardiac (13.8%) for all symptomatic patients (n = 240); neurologic (67.8%), mixed (21.2%), and cardiac (11.0%) for symptomatic Val30Met (n = 146); and mixed (64.9%), cardiac (22.8%), and neurologic (12.3%) for symptomatic ATTRwt (n = 57). Symptomatic patients reported a range of ATTR amyloidosis signs and symptoms at enrollment, with autonomic neuropathy and sensory neuropathy common in all phenotypes.ConclusionsThese results from THAOS highlight the phenotypic heterogeneity associated with ATTR amyloidosis in Spain and the importance of comprehensive neurologic and cardiac evaluations in all patients with ATTR amyloidosis.Trial registrationClinicalTrials.gov: NCT00628745.

Dataset Information

A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics.

Publications

A library of ATTR amyloidosis patient-specific induced pluripotent stem cells for disease modelling and in vitro testing of novel therapeutics.

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