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Endothelial-targeted recombinant CD39 as novel therapy for brain ischaemia

1Australian Centre for Blood Diseases and Monash University, Melbourne, Victoria, Australia, 2Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia, 3Monash University, Melbourne, Victoria, Australia, 4Department of Neurosciences, Monash University, Melbourne, Victoria, Australia, 5Baker Institute, University of Melbourne, Melbourne, Victoria, Australia, 6Harvard University, Boston, Massachusetts, United States, 7Alfred Health and the Australian Centre for Blood Diseases and Monash University, Melbourne, Victoria, Australia

Abstract Number: OC 45.5

Meeting: ISTH 2022 Congress

Theme: Arterial Thromboembolism » Cerebrovascular Disorders

Background: Ischaemia-reperfusion injury (IRI) contributes to acute ischaemic stroke (AIS) as well as to hypoxia induced brain injury (HIBI) that follows delayed resuscitation post cardiopulmonary arrest. IRI contains inflammation, thrombosis and activation of endothelium (EC).

‘Anti-VCAM-CD39’ is designed to target the antiinflammatory and antithrombotic properties of soluble CD39 (previously demonstrated by others and us) to activated EC by the incorporation of a scFV tag recognising the EC activation receptor VCAM-1. CD39 activity hydrolyses ATP and ADP to AMP with subsequent conversion to adenosine.

Aims: To demonstrate that anti-VCAM-CD39 will improve stroke outcomes in murine models of AIS and HIBI when given as a single agent, and maximise the benefit of tPA in AIS. Doses on anti-VCAM-CD39 used here do not perturb haemostasis.

Methods: Models of transient middle cerebral artery occlusion (MCAo) and of global forebrain ischaemia by dual carotid artery ligation (DCAL) were utilised (models published by us: Scientific reports, 2020; 10, 1-13).

The test drugs (anti-VCAM-CD39 and various controls were given after 3 hours after ischaemia of 30 min.

Assessments at 24 h included function (Bederson score and footslips), infarct volume and perfusion (MRI), albumin extravasation and serum vWF.

Results: In the HIBI (DCAL) model, anti-VCAM-CD39 (0.125mg/kg) demonstrated small infarct volumes, lesser albumin extravasation and caspase activation and lower plasma vWF compared with saline and anti-VCAM-Inactive CD39 (controls) (data and statistics as shown in (Fig.1) and lower neurological deficit score (Saline: 4, n=19; anti-VCAM_CD39: 2, n=14, p=0.0001, One-way ANOVA).

In the MCAo model, anti-VCAM-CD39 (0.5mg/kg), demonstrated lower infarct volumes and better perfusion (Fig 2), lower albumin extravasation and vWF level p < 0.5 for all parameters). Co-administration with tPA was synergistic in improving function and infarct volumes (p < 0.05).

Conclusion(s): Endothelial-targeted soluble CD39 (at a dose that dose that does not perturb haemostasis) significantly improved outcomes in focal stroke as well as global brain ischaemia.

To cite this abstract in AMA style:

Lee N, Selan C, Chia J, Medcalf R, Wright D, Wang X, Peter K, Robson S, Sashindranath M, Nandurkar H. Endothelial-targeted recombinant CD39 as novel therapy for brain ischaemia [abstract]. https://abstracts.isth.org/abstract/endothelial-targeted-recombinant-cd39-as-novel-therapy-for-brain-ischaemia/. Accessed October 1, 2023.

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