Drug Insight: emerging therapies for amyloidosis

Abstract

Amyloidosis is a clinical disorder caused by extracellular deposition of proteins that are normally soluble as insoluble, abnormal fibrils that impair organ function. More than 20 unrelated proteins can form amyloid fibrils in vivo. All fibrils share cross-beta core structure and pathognomonic red-green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloidosis can be acquired or hereditary, localized or systemic, and is classified according to the fibril precursor protein. Local amyloid deposition occurs in the brain in Alzheimer's disease and in the pancreas in maturity-onset diabetes, but a direct role in the pathogenesis of these diseases remains unproven. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls and connective tissues, is usually fatal and is the cause of about one death per thousand in developed countries. Recent elucidation of fundamental aspects of the pathogenesis of amyloidosis, and developments in diagnosis and monitoring of this disorder have greatly improved outcome for patients. Several exciting novel therapeutic strategies, reviewed in this article, are in development. These include interference with different stages of fibrillogenesis and enhancement of clearance of amyloid deposits.