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Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

ABSTRACT: Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

SUBMITTER: Ferreira N

PROVIDER: S-EPMC4873750 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

Ferreira Nelson N Gonçalves Nádia P NP Saraiva Maria J MJ Almeida Maria R MR

Scientific reports 20160520

Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically ach ...[more]

PMID: 27197872

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Project description:AimsCardiac transthyretin amyloidosis (ATTR-CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow-up and whether it maintains its prognostic value throughout the disease course.Methods and resultsWe performed a retrospective study of 945 patients with wild-type ATTR-CM (wtATTR-CM) or hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease-modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan-Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow-up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR-CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95-2.67; P < 0.001; Stage III vs. II, HRs 1.64-2.25; P < 0.001-0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow-up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58-3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86-4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I-hATTR-CM than in wtATTR-CM (43% vs. 27% at 12 months of follow-up; P = 0.003).ConclusionsNational Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR-CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow-up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I-hATTR-CM than in wtATTR-CM.

Project description:IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early- or late-onset disease.MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late- (age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019).ResultsOf 1389 patients with ATTRv Val30Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Late-onset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in late-onset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% early-onset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p < 0.001).ConclusionIn THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to more timely diagnosis and improve patient outcomes.Trial registrationClinicalTrials.gov NCT00628745.

Project description:Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients' nutritional status and health-related quality of life (HRQoL).The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL.Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p?<?0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p?<?0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p?<?0.001 for all).Gastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances.

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Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

Publications

Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.

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