OC 45.5 - Endothelial-targeted recombinant CD39 as novel therapy for brain ischaemia

Monday, July 11, 2022

3:45 PM – 4:00 PM

Location: ExCel Center, ICC Capital Suite Room 8&9

Presentation Format: In-Person

Co-Author(s)

NL

Natasha Lee

Post doctoral scientist
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
CS

Carly Selan

Research Assistant
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
JC

Joanna Chia

Research Assistant
Australian Centre for Blood Diseases
Melbourne, Victoria, Australia
Robert L. Medcalf, PhD

Laboratory Director
Monash University
Melbourne, Victoria, Australia
DW

David Wright

Laboratory Head
Department of Neurosciences, Monash University
Melbourne, Victoria, Australia
XW

Xiaowei Wang

Laboratory Head
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
KP

Karlheinz Peter

Deputy Director, Basic and Translational Science
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
SR

Simon Robson

Professor of Anaesthesia, Charlotte F. & Irving W. Rabb Distinguished Professor of Gastroenterology
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
MS

Maithili Sashindranath

Senior Scientist and Deputy Lab Head
Australian Centre for Blood Diseases and Monash University
Melbourne, Victoria, Australia

Presenting Author(s)

Harshal Nandurkar, MD, PhD, FRACP, FRCPA

Director of Clinical Haematology, Alfred Health. Head of the Australian Centre for Blood Diseases
Alfred Health and Monash University
Melbourne, Victoria, Australia

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.