Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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Background: 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. ⋯ At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres. Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.
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Response assessment in light chain (AL) amyloidosis is challenging given the low level of circulating free light chains usually seen. Multi-parametric flow cytometry (MFC) from a marrow aspirate was demonstrated to retain a prognostic significance in several recent studies. ⋯ Absence of clonal plasma cells by MFC compared with patients with detectable clonal plasma cells among deep responders was associated with lower level of involved light chain (involved free light chain (iFLC), median 1.1 vs. 1.7 mg/dL; p = .02) and higher frequency of renal response (100% vs. 68%; p = .005). Further studies are needed to determine if MFC should be incorporated into response criteria in AL amyloidosis.
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Pragmatic Clinical Trial
Immunoelectron microscopy and mass spectrometry for classification of amyloid deposits.
Amyloidosis is a shared name for several rare, complex and serious diseases caused by extra-cellular deposits of different misfolded proteins. Accurate characterization of the amyloid protein is essential for patient care. Immunoelectron microscopy (IEM) and laser microdissection followed by tandem mass spectrometry (LMD-MS) are new gold standards for molecular subtyping. ⋯ Concordance was 89.6-100% for different amyloid subtypes. Importantly, combined use of both methods increased the diagnostic classification to 100%. Some variety in performances at organ level was observed.
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The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease. ⋯ Analysis of APOE polymorphisms in ATTR amyloidosis patients revealed three most frequent genotypes E3/3, E3/4 and E3/2. APOE stratification of patients did not show significant differences of TTR plasma concentrations following treatment. Our results suggest that APOE is an important mediator of TTR silencing by Patisiran, however efficacy is independent of the APOE genotype.
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Letter Case Reports
Coexistence of wild type and hereditary ATTR amyloidosis in one family.