Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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Serum and urine immunofixation electrophoreses (SIFE/UIFE) are used for clonal detection in plasma cell dyscrasias, while serum free light chain (sFLC) testing provides quantitation of clonal disease. Up to 20% of patients with light chain (AL) amyloidosis may present with normal FLC ratio (FLCr). ⋯ The HLC assay has potential as a supplemental test to quantify monoclonal protein in patients with normal FLCr results.
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Some TTR mutants target the central nervous system (CNS). Familial amyloid polyneuropathy (FAP) with leptomeningeal involvement has been described in 9% of transthyretin (TTR) mutations and in valine for methionine at position 30 (V30M) patients. These individuals present dementia, ataxia, brain hemorrhages and focal neurological episodes (FNEs). ⋯ We show that systemically administered TTR siRNA promoted TTR clearance in the extracellular matrix of meninges and brain blood vessels. Surprisingly, despite the striking decline of blood TTR, cerebrospinal fluid TTR levels were unaffected. Though this is reassuring because siRNA will not interfere with the neuroprotective role of TTR in the CNS, it raises new questions on therapeutical approaches for CNS ATTR.
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Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease that results from the deposition of misfolded transthyretin (TTR) protein from the plasma into tissues as amyloid fibrils, leading to polyneuropathy and cardiomyopathy. IONIS-TTRRx (ISIS 420915) is a 2nd-Generation 2'-O-(2-methoxyethyl) modified "2'-MOE" antisense oligonucleotide (ASO) that targets the TTR RNA transcript and reduces the levels of the TTR transcript through an RNaseH1 mechanism of action, leading to reductions in both mutant and wild-type TTR protein. The activity of IONIS-TTRRx to decrease TTR protein levels was studied in transgenic mice bearing the Ile84Ser human TTR mutant, in cynomolgus monkeys and in healthy human volunteers. ⋯ In a Phase 1 healthy volunteer study, treatment with IONIS-TTRRx for four weeks was well tolerated without any remarkable safety issues. TTR protein reductions up to 96% in plasma were observed. These nonclinical and clinical results support the ongoing Phase 3 development of IONIS-TTRRx in patients with ATTR amyloidosis.
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Leukocyte chemotactic factor 2 (LECT2) amyloidosis is one of the most recently described types of amyloidosis. Since its description, it has been found to be one the most common types of amyloidosis in large series of amyloid cases involving the kidney and liver in the United States, where it primarily affects patients of Hispanic ethnicity. ⋯ It was consistently deposited in the liver, spleen, adrenals, and lungs but did not involve the myocardium or brain. LECT2 amyloidosis is likely not rare among Hispanics in the Southwest United States and could represent an important but under-recognized etiology of chronic kidney disease in this population.
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Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. ⋯ We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity.