Melanie Ziegler1, Jan David Hohmann1, Amy Kate Searle1,2, Meike-Kristin Abraham1,3, Harshal H Nandurkar2,4, Xiaowei Wang1,2, Karlheinz Peter1,2. 1. Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC 3004, Australia. 2. Department of Medicine, Monash University, Melbourne, VIC 3800, Australia. 3. Department of Thoracic, Cardiac and Vascular Surgery, Clinical Research Laboratory, University Hospital Tübingen, Calwerstr. 7/1, 72076 Tübingen, Germany. 4. Australian Centre for Blood Diseases, Central Clinical School, Alfred Hospital, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia.
Abstract
Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis. Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling. Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction. Published on behalf of the European Society of Cardiology. All rights reserved.
Aims: CD39 is a cell membrane NTPase with anti-inflammatory and anti-platelet effects. However, its clinical use is limited by its bleeding side effect. With the goal of harnessing its therapeutic potential while avoiding haemostatic problems, we designed a fusion protein consisting of the extracellular domain of CD39 and a single-chain antibody (Targ-CD39) that specifically binds to activated glycoprotein (GP)IIb/IIIa and thus to activated platelets. Through this enrichment at activated platelets, the required systemic dose is below the dose impairing haemostasis. Methods and results: Using an ischaemia/reperfusion mouse model (left anterior descending artery ligated for 1 h) we achieved remarkable protection of the reperfused tissue with Targ-CD39 compared with Non-targ-CD39 (mutated, non-binding version of Targ-CD39) and PBS control. Targ-CD39 restored ejection fraction and fractional shortening to a level indistinguishable from pre-injury status, while controls showed functional deterioration. Employing advanced clinically relevant methods of ultrasound analysis, we observed that both radial and longitudinal strain and strain rate showed infarct-typical changes of myocardial deformation in controls, but not in Targ-CD39 treated mice. Histological assessment confirmed strong reduction of infarct size and increase in neovascularization. Furthermore, attenuation of post-ischaemic inflammation was seen in cytokine profiling. Conclusion: Overall, we demonstrate that Targ-CD39 holds promise for treatment of myocardial infarction. Published on behalf of the European Society of Cardiology. All rights reserved.
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