Journal Article

DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis

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

2017

Overview

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. DEK is a secreted protein abundant in the synovia of patients with juvenile idiopathic arthritis. Here the authors show DEK is important for neutrophil extracellular trap formation and joint inflammation, and demonstrate therapeutic efficacy of DEK-targeting aptamers in a mouse model of arthritis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/21 / 13/31 / 14/1 / 14/19 / 14/34 / 14/63 / 631/250/2504/223/1699 / 692/4023/1670/3 / 692/4023/1670/427/1304 / Adult / Animals / Aptamers, Nucleotide - therapeutic use / Arthritis / Arthritis, Juvenile - immunology / Arthritis, Juvenile - therapy / Biology / Bone marrow / Chemotactic Factors - antagonists & inhibitors / Chemotactic Factors - genetics / Chemotactic Factors - immunology / Chemotactic Factors - metabolism / Chromosomal Proteins, Non-Histone - antagonists & inhibitors / Chromosomal Proteins, Non-Histone - genetics / Chromosomal Proteins, Non-Histone - immunology / Chromosomal Proteins, Non-Histone - metabolism / Chronic illnesses / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA-Binding Proteins - antagonists & inhibitors / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Extracellular Traps - immunology / Extracellular Traps - metabolism / Female / Healthy Volunteers / Humanities and Social Sciences / Humans / Infectious diseases / Internal medicine / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Neutrophils / Neutrophils - immunology / Oncogene Proteins - antagonists & inhibitors / Oncogene Proteins - genetics / Oncogene Proteins - immunology / Oncogene Proteins - metabolism / Pathogenesis / Poly-ADP-Ribose Binding Proteins - antagonists & inhibitors / Poly-ADP-Ribose Binding Proteins - genetics / Poly-ADP-Ribose Binding Proteins - immunology / Poly-ADP-Ribose Binding Proteins - metabolism / Primary Cell Culture / Proteins / Rheumatology / Science / Science (multidisciplinary) / Synovial Fluid - chemistry / Synovial Fluid - cytology / Synovial Fluid - immunology / Tumor necrosis factor-TNF / Zymosan - immunology