Preventing stroke from arteriovenous malformations using precision thrombosis

    Project: Research

    Project Details


    Our vision is to develop a vascular targeting approach to treat brain arteriovenous malformations (AVMs). AVMs are collections of fragile, rupture-prone blood vessels that occur in the brain that are a significant cause of stroke in children and young adults. Most small AVMs are curable by surgical removal or radiosurgery-induced occlusion, but most large AVMs are untreatable, leaving one third of these young AVM patients at constant risk of sudden death or
    lifelong neurological disability. There is a high unmet medical need for innovative treatment approaches that would reduce the morbidity and mortality of this disease. The aim of this study is the develop a series of vascular targeting agents that can deliver a thrombotic molecule to the abnormal AVM vessels to induce localised thrombosis, occlusion and cure. Focused radiosurgery is used to
    induce molecular changes on the abnormal endothelium. To date we have identified a series of putative radiationstimulated targets and recently demonstrated successful occlusive thrombosis using a prototypical targeting agent in a preclinical model, demonstrating proof-of-concept. To advance this technology toward clinical translation, our aim is to develop an expanded series of novel vascular targeting agents to further investigate how target, ligand and
    thrombotic effector combinations affect therapeutic efficacy, selectivity and safety. We will investigate targeting of our existing molecular target, exposed phosphatidylserine, and two new targets, the mitochondrial E2 subunit of
    pyruvate dehydrogenase, and the intracellular chaperone, alpha-B-crystallin. These normally intracellular molecules are translocated to the cell surface in response to radiation and are highly prospective as targets given their absence on the normal healthy endothelium. We will use our established in vitro blood circulation system for conjugate development and pre-testing before application to the our established rat AVM model.
    Effective start/end date1/01/2131/12/24