Drug Insight: Emerging Therapies for Amyloidosis
Drug Insight: Emerging Therapies for Amyloidosis
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-β 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.
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as insoluble fibrils that have a characteristic, highly ordered abnormal conformation that progressively disrupts tissue structure and impairs function. Some 20 different unrelated proteins can form amyloid in vivo, and clinical amyloidosis is classified according to the fibril protein type ( Table 1 ).
Amyloid deposition can be systemic or localized, and life-threatening or merely an incidental finding. Systemic amyloidosis, in which deposits can occur in any organ except the brain, remains potentially fatal despite increasingly effective treatment of conditions that underlie amyloid deposition and improvements in organ-specific supportive measures. Localized amyloidosis, in which deposits are confined to specific foci or to a particular organ or tissue, is often clinically silent but can be associated with serious disease, such as hemorrhage in local respiratory or urogenital tract AL amyloid.
Local amyloid deposits are also hallmark pathological features of Alzheimer's disease, type 2 diabetes mellitus and prion disorders in which the pathogenetic role of the amyloid remains unclear. Although these conditions will not be discussed in detail in this Review, it should be noted that emerging therapeutic strategies for systemic amyloidosis aimed at inhibiting amyloid fibrillogenesis, promoting regression of amyloid deposits, or both, might also be applicable to these diseases.
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-β 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.
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as insoluble fibrils that have a characteristic, highly ordered abnormal conformation that progressively disrupts tissue structure and impairs function. Some 20 different unrelated proteins can form amyloid in vivo, and clinical amyloidosis is classified according to the fibril protein type ( Table 1 ).
Amyloid deposition can be systemic or localized, and life-threatening or merely an incidental finding. Systemic amyloidosis, in which deposits can occur in any organ except the brain, remains potentially fatal despite increasingly effective treatment of conditions that underlie amyloid deposition and improvements in organ-specific supportive measures. Localized amyloidosis, in which deposits are confined to specific foci or to a particular organ or tissue, is often clinically silent but can be associated with serious disease, such as hemorrhage in local respiratory or urogenital tract AL amyloid.
Local amyloid deposits are also hallmark pathological features of Alzheimer's disease, type 2 diabetes mellitus and prion disorders in which the pathogenetic role of the amyloid remains unclear. Although these conditions will not be discussed in detail in this Review, it should be noted that emerging therapeutic strategies for systemic amyloidosis aimed at inhibiting amyloid fibrillogenesis, promoting regression of amyloid deposits, or both, might also be applicable to these diseases.