Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis

Barbara Kluve-Beckerman, Joyce Hardwick, Lijing Du, Merrill D. Benson, Brett P. Monia, Andrew Watt, Rosanne M. Crooke, Adam Mullick

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

AA amyloid patients who experience disease progression and develop renal failure have not received sufficient benefit from agents that treat inflammation or infection. We have begun to explore the potential application of antisense oligonucleotides (ASOs) to specifically suppress SAA production and thereby reduce amyloid deposition. Proof-of-concept experiments conducted in mice initially examined ASO ability to reduce serum levels of SAA during an acute inflammatory response. Peak SAA levels in ASO-treated mice were reduced as much as 65% relative to levels in saline-treated mice. The extent of suppression was dose-dependent and influenced by the time interval between ASO administration and inflammatory stimulation. Subsequent experiments tested whether ASO suppression of SAA was sufficient to mitigate amyloid deposition. Amyloidosis was induced by amyloid-enhancing factor and silver nitrate injection; ASO treatment was initiated 1 week later and continued 1× or 3× per week; inflammation was re-triggered by subsequent injection(s) of silver nitrate; mice were sacrificed after 45 weeks. Examination of tissues by Congo red staining and SAA/AA immunohistochemistry revealed consistently less amyloid in the organs of ASO-treated mice compared to saline-treated counterparts. These findings provide rationale for further investigation of SAA-specific ASOs as a potential therapy for AA amyloidosis.

Original languageEnglish (US)
Pages (from-to)136-146
Number of pages11
JournalAmyloid
Volume18
Issue number3
DOIs
StatePublished - Sep 1 2011

Keywords

  • AA amyloidosis
  • Antisense oligonucleotide
  • Mouse model
  • Serum amyloid A

ASJC Scopus subject areas

  • Internal Medicine

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    Kluve-Beckerman, B., Hardwick, J., Du, L., Benson, M. D., Monia, B. P., Watt, A., Crooke, R. M., & Mullick, A. (2011). Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis. Amyloid, 18(3), 136-146. https://doi.org/10.3109/13506129.2011.597464