DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis

Nirit Mor-Vaknin (), Anjan Saha, Maureen Legendre, Carmelo Carmona-Rivera, M Asif Amin, Bradley J. Rabquer, Marta J. Gonzales-Hernandez, Julie Jorns, Smriti Mohan, Srilakshmi Yalavarthi, Dave A. Pai, Kristine Angevine, Shelley J. Almburg, Jason S. Knight, Barbara S. Adams, Alisa E. Koch, David A. Fox, David R. Engelke, Mariana J. Kaplan and David M. Markovitz
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Nirit Mor-Vaknin: University of Michigan
Anjan Saha: University of Michigan
Maureen Legendre: University of Michigan
Carmelo Carmona-Rivera: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases
M Asif Amin: University of Michigan
Bradley J. Rabquer: University of Michigan
Marta J. Gonzales-Hernandez: University of Michigan
Julie Jorns: University of Michigan
Smriti Mohan: University of Michigan
Srilakshmi Yalavarthi: University of Michigan
Dave A. Pai: University of Michigan
Kristine Angevine: University of Michigan
Shelley J. Almburg: Microscopy & Image – Analysis Laboratory, University of Michigan
Jason S. Knight: University of Michigan
Barbara S. Adams: University of Michigan
Alisa E. Koch: University of Michigan
David A. Fox: University of Michigan
David R. Engelke: University of Michigan
Mariana J. Kaplan: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases
David M. Markovitz: University of Michigan

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Novel therapeutics are required for improving the management of chronic inflammatory diseases. Aptamers are single-stranded RNA or DNA molecules that have recently shown utility in a clinical setting, as they can specifically neutralize biomedically relevant proteins, particularly cell surface and extracellular proteins. The nuclear chromatin protein DEK is a secreted chemoattractant that is abundant in the synovia of patients with juvenile idiopathic arthritis (JIA). Here, we show that DEK is crucial to the development of arthritis in mouse models, thus making it an appropriate target for aptamer-based therapy. Genetic depletion of DEK or treatment with DEK-targeted aptamers significantly reduces joint inflammation in vivo and greatly impairs the ability of neutrophils to form neutrophil extracellular traps (NETs). DEK is detected in spontaneously forming NETs from JIA patient synovial neutrophils, and DEK-targeted aptamers reduce NET formation. DEK is thus key to joint inflammation, and anti-DEK aptamers hold promise for the treatment of JIA and other types of arthritis.

Date: 2017
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DOI: 10.1038/ncomms14252

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