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Occlusion of Animal Model Arteriovenous Malformations Using Vascular Targeting

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Abstract

Brain arteriovenous malformations (AVMs) are a significant cause of intracerebral hemorrhage in children and young adults. Currently, one third of patients have no viable treatment options. Vascular targeting agents (VTAs) are being designed to deliver pro-thrombotic molecules to the abnormal AVM vessels for rapid occlusion and cure. This study assessed the efficacy of a pro-thrombotic VTA targeting phosphatidylserine (PS) in a radiation-primed AVM animal model. The model AVM was surgically created in rats by anastomosis of the left external jugular vein to the adjacent common carotid artery. After 6 weeks, the AVM was irradiated (20 Gy) using gamma knife surgery (GKS). A PS-targeting VTA was created by conjugation of annexin V with human thrombin and administered intravenously 3 weeks post-GKS or sham. Unconjugated thrombin was used as a non-targeting control. AVM thrombosis and occlusion was monitored 3 weeks later by angiography and histology. Preliminary experiments established a safe dose of active thrombin for systemic administration. Subsequently, a single dose of annexin V–thrombin conjugate (0.77 mg/kg) resulted in angiographic AVM occlusion in sham (75%) and irradiated (63%) animals, while non-targeted thrombin did not. Lowering the conjugate dose (0.38 mg/kg) decreased angiographic AVM occlusion in sham (13%) relative to irradiated (80%) animals (p = 0.03) as did delivery of two consecutive doses of 0.38 mg/kg, 2 days apart (sham (0%); irradiated (78%); p = 0.003). These findings demonstrate efficacy of the PS-targeting VTA and the feasibility of a vascular targeting approach for occlusion of high-flow AVMs. Targeting specificity can be enhanced by radiation–sensitization and VTA dose modification.

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Acknowledgments

This work was supported by a grant from the National Health and Medical Research Council of Australia (to M.A.S.; APP1047302 and APP1085045). A.G. was supported by an Avant Doctor in Training Research Scholarship (2015–2017) and a National Health and Medical Research Council Research Scholarship (2015–2018).

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Authors and Affiliations

  1. Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Neurosurgery Unit, Suite 201, 2 Technology Place, Sydney, NSW, 2109, Australia

    Andrew J. Gauden, Lucinda S. McRobb, Vivienne S. Lee, Sinduja Subramanian, Zhenjun Zhao & Marcus A. Stoodley

  2. Genesis Cancer Care, Macquarie University Hospital, Sydney, 2109, Australia

    Vaughan Moutrie

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  1. Andrew J. Gauden
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  7. Marcus A. Stoodley
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by A.G., V.L., L.M., Z.Z., and S.S. The first draft of the manuscript was prepared by A.G. and L.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Marcus A. Stoodley.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted (Macquarie University Animal Care and Ethics Committee, Sydney, Australia; AEC reference 2015/026).

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Gauden, A.J., McRobb, L.S., Lee, V.S. et al. Occlusion of Animal Model Arteriovenous Malformations Using Vascular Targeting. Transl. Stroke Res. 11, 689–699 (2020). https://doi.org/10.1007/s12975-019-00759-y

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  • DOI: https://doi.org/10.1007/s12975-019-00759-y

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