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Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

Mariana Conceição, Laura Forcina, Oscar P. B. Wiklander, Dhanu Gupta, Joel Z. Nordin, Graham McClorey, Imre Mäger, André Görgens, Per Lundin, Antonio Musarò, View ORCID ProfileMatthew J. A. Wood, Samir EL Andaloussi, View ORCID ProfileThomas C. Roberts
doi: https://doi.org/10.1101/2020.06.09.142216
Mariana Conceição
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Department of Paediatrics, University of Oxford, Oxford, UK
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  • For correspondence: mariana.conceicao@paediatrics.ox.ac.uk thomas.roberts@paediatrics.ox.ac.uk
Laura Forcina
3DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, IMM, Sapienza University of Rome, Rome, Italy
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Oscar P. B. Wiklander
4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
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Dhanu Gupta
4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
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Joel Z. Nordin
4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
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Graham McClorey
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Department of Paediatrics, University of Oxford, Oxford, UK
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Imre Mäger
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Department of Paediatrics, University of Oxford, Oxford, UK
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André Görgens
4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
6Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
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Per Lundin
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
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Antonio Musarò
3DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, IMM, Sapienza University of Rome, Rome, Italy
7Center for Life Nano Science @Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
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Matthew J. A. Wood
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Department of Paediatrics, University of Oxford, Oxford, UK
8MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
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  • ORCID record for Matthew J. A. Wood
Samir EL Andaloussi
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
5Evox Therapeutics Limited, Oxford Science Park, Oxford, UK
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Thomas C. Roberts
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Department of Paediatrics, University of Oxford, Oxford, UK
8MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
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  • ORCID record for Thomas C. Roberts
  • For correspondence: mariana.conceicao@paediatrics.ox.ac.uk thomas.roberts@paediatrics.ox.ac.uk
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Abstract

The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

Competing Interest Statement

MJAW and SEA are founders of, and consultants for, Evox Therapeutics. IM, AG, and DG are consultants for Evox Therapeutics. MJAW, SEA, JZN, OW, AG, and DG are shareholders in Evox Therapeutics. The remaining authors declare no conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 10, 2020.
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Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle
Mariana Conceição, Laura Forcina, Oscar P. B. Wiklander, Dhanu Gupta, Joel Z. Nordin, Graham McClorey, Imre Mäger, André Görgens, Per Lundin, Antonio Musarò, Matthew J. A. Wood, Samir EL Andaloussi, Thomas C. Roberts
bioRxiv 2020.06.09.142216; doi: https://doi.org/10.1101/2020.06.09.142216
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Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle
Mariana Conceição, Laura Forcina, Oscar P. B. Wiklander, Dhanu Gupta, Joel Z. Nordin, Graham McClorey, Imre Mäger, André Görgens, Per Lundin, Antonio Musarò, Matthew J. A. Wood, Samir EL Andaloussi, Thomas C. Roberts
bioRxiv 2020.06.09.142216; doi: https://doi.org/10.1101/2020.06.09.142216

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