# Pathogenesis and Treatment of AA Amyloidosis > **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · — ## Abstract AA (secondary, reactive) amyloidosis is a disease caused by extracellular deposition of insoluble β-pleated sheet fibrils composed of amyloid A (AA) protein, an N-terminal fragment of the acute phase protein serum amyloid A (SAA). The deposits disrupt tissue structure and eventually compromise organ function. Common sites of deposition include kidney, spleen, liver, and intestine. In humans proteinuria due to glomerular deposits is often the first clinical manifestation, and with increasing deposition, the nephrotic syndrome usually progresses to end-stage renal disease. AA amyloidosis usually develops as a complication of chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and the hereditary auto-inflammatory syndromes (e.g., familial Mediterranean fever). It also occurs in association with long-standing infections (osteomyelitis, decubitus ulcers, bronchiectasis). Veterans with paraplegia are at risk of developing AA amyloidosis due to chronic decubitus ulcers, urinary tract infections and osteomyelitis. In addition, ankylosing spondylitis is common in our male veterans which also increases risk for AA amyloidosis. At present, there is no specific therapy for AA amyloidosis. Only control of pro-inflammatory stimuli to reduce hepatic SAA synthesis has shown an effect on AA amyloid progression. In a recent Phase III clinical trial, a potential new therapy [eprodisate (Kiacta)] failed to show significance in retarding AA progression. Prompted by the unmet needs of patients, our initial aim will be to initiate development of a therapy for AA amyloidosis using as framework translational studies we have conducted on transthyretin (TTR) amyloidosis. The therapeutic strategy will be administration of human SAA-specific antisense oligonucleotides (ASO) that facilitate degradation of SAA mRNA resulting in lower SAA levels in blood and less substrate available for amyloid formation. A transgenic mouse model carrying a human SAA1 genomic segment encompassing SAA1 promoter and regulatory elements will be generated and employed for this study. Human SAA1-specific ASOs will be provided by Ionis Pharmaceuticals and screened for ability to downregulate SAA1 expression in human cell cultures. Promising compounds will be conjugated with N-acetyl galactosamine (GalNAc); this modification confers targeted delivery to the liver and increases potency 6-10-fold, allowing for lower dosing. After further screening in normal mice to evaluate tolerability, ASOs will be given to human SAA1 transgenic mice to determine the level of suppression achieved at various doses. The human SAA1 transgenic mice we generate will be crossed with mice that do not express mouse SAA1 or SAA2; these mice will be provided by Drs. Frederick de Beer and Nancy Webb, University of Kentucky. The offspring of this cross-breeding, i.e., mice expressing human SAA1 but not mouse SAA1 or SAA2, will be induced to develop AA amyloidosis using... ## Key facts - **NIH application ID:** 9932316 - **Project number:** 5I01CX001631-03 - **Recipient organization:** RLR VA MEDICAL CENTER - **Principal Investigator:** MERRILL D BENSON - **Activity code:** I01 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2020 - **Award amount:** — - **Award type:** 5 - **Project period:** 2018-07-01 → 2022-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9932316 ## Citation > US National Institutes of Health, RePORTER application 9932316, Pathogenesis and Treatment of AA Amyloidosis (5I01CX001631-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932316. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*