AA amyloidosis (reactive, secondary) is caused by the extracellular deposition of protein fibrils which disrupts normal organ function and usually leads to death from renal, hepatic or cardiac failure. It is a serious complication of many chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, regional enteritis (Crohn's disease), and inherited recurrent febrile diseases such as the autosomal recessive familial Mediterranean fever (FMF), and a group of autosomal dominant syndromes including TNF-alpha receptor associated periodic syndrome (TRAPS), Muckle-Wells syndrome, familial cold urticaria (FCAS), and hyper- immunoglobulin D syndrome. It is also a fatal complication of chronic infectious diseases such as osteomyelitis in patients with paraplegia or quadriplegia. All of these diseases, whether acquired or genetic, cause recurrent inflammation resulting in elevated expression of the acute phase proteins of the serum amyloid A (SAA) family. SAA, an apolipoprotein of plasma HDL, is the precursor of the amyloid fibril subunit AA. The current understanding of the pathogenesis of AA amyloidosis is that SAA, a single polypeptide of 104 amino acid residues, which is overproduced during chronic inflammation, is partially proteolyzed, and the amino-terminal 1- 76 residues aggregate to form insoluble fibrils. These fibril deposits then compromise normal tissue function and lead to progressive organ failure. While considerable progress has been made in understanding the pathogenic mechanisms involved in AA amyloid formation, no specific therapy for this disease has been developed. In AA patients with chronic inflammatory diseases treatment with agents to decrease inflammation have been the mainstay for treating the primary disease with the projection that reduction in SAA blood levels will curtail the formation of AA amyloid deposition. Considerable clinical evidence suggests that reduction in inflammatory markers, including serum amyloid A, may prevent or slow the progression of AA amyloidosis;however, many patients do not have complete response to anti-inflammatory agents including immunosuppressive and anti-TNF biologic agents. This is a group of chronic disease patients that develop amyloidosis. While control of inflammation may prevent the development of AA amyloidosis, once the process has started effective means of altering progression are not known. The overall objective of this proposal is to develop specific therapeutic strategies to alter progression of AA amyloidosis. This will be explored in two lines of investigation:
Aim 1) Use a cell culture model of AA amyloid fibril formation to define the mechanisms by which anti-TNF agents may inhibit AA amyloid deposition. Anecdotal reports suggest that anti-TNF agents may inhibit AA amyloid progression in ways other than just their ability to suppress the inflammatory response.
Aim 2) Use a murine model of AA amyloidosis to test the hypothesis that reduction of hepatic synthesis of SAA by specific antisense oligonucleotides (ASO) can reduce SAA and stop progression of amyloid fibril formation by limiting availability of AA fibril precursor. Successful completion of these aims will offer a basis for development of specific therapeutics to treat this fatal disease.
Chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, granulomatous bowel disease, and infectious diseases are common in the Veteran population. Reactive (secondary) amyloidosis is a significant complication of these diseases and is usually fatal. Veterans with paraplegia often have chronic infections such as osteomyelitis and, therefore, have an increased incidence of AA amyloidosis. Since reactive amyloidosis very often leads to renal failure, chronic dialysis is required and significantly adds to health care costs in patients with this progressive fatal disease. The Veteran population also has an increase in prevalence of the age related amyloidoses including immunoglobulin amyloid, Alzheimer disease and senile cardiac amyloidosis. Understanding the pathogenesis of the reactive form of amyloidosis may reveal avenues for treatment of not only AA amyloidosis but also other forms of amyloidosis in the Veteran population.