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Journal Article
Review
Systemic amyloidosis: novel therapies and role of biomarkers.
Nephrology, Dialysis, Transplantation 2017 May 2
Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future.
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