DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis

Nirit Mor‐Vaknin ,Barbara S Adams,Anjan K Saha ,Mariana J Kaplan,Kristine Angevine,M Asif Amin ,Dave A Pai,Julie M Jorns ,Smriti Mohan,Marta J Gonzales-Hernandez ,David A Fox,Shelley J Almburg ,Maureen Legendre,Jason S Knight,Bradley J Rabquer,David R Engelke,Alisa E Koch,Srilakshmi Yalavarthi,Carmelo Carmona-Rivera,David M Markovitz

doi:10.1038/ncomms14252

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.

Highlights

Novel therapeutics are required for improving the management of chronic inflammatory diseases
We demonstrated that DEK is secreted, but can enter neighbouring cells by a heparan-sulfate peptidoglycan-dependent pathway and correct the global heterochromatin and DNA repair defects seen in DEK knockdown cells[7,8]
Using the Zymosan-induced arthritis (ZIA) mouse model[17], we found that Dek-KO mice are significantly less likely than WT mice to develop arthritis, and single-stranded anti-DEK DNA aptamers markedly attenuate inflammation in WT mice subjected to ZIA

Summary

Introduction

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 neutralize biomedically relevant proteins, 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). DEK is key to joint inflammation, and anti-DEK aptamers hold promise for the treatment of JIA and other types of arthritis. Mechanistic insight into the chronic joint inflammation characteristic of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) is severely lacking, warranting a need for identifying novel targets that carry therapeutic promise. An attractive therapeutic avenue involves the use of aptamers, which are single-stranded DNA or RNA oligonucleotides that can be designed to target and inactivate clinically relevant molecules. Proof of a direct role for DEK in inflammation has, been lacking

Methods

Results

Conclusion