Vascular targeting in an arteriovenous malformation animal model

Theoretical thesis.Bibliography: pages 204-228.Chapter 1 Literature review -- Chapter 2. Methods -- Chapter 3. Annexin V/T hrombin conjugate optimisation -- Chapter 4. Vascular targeting of PS in the AVM animal model -- Chapter 5. Dose modification increases targeting selectivity -- Chapter 6. Preliminary validation of novel radiation-induced vascular target -- Chapter 7. General discussions and future directions.Brain arteriovenous malformations (AVMs) pose a significant lifetime risk of haemorrhagic stroke that preferentially affects children and young adults. Despite the current available treatments of surgical excision, approximately one third of AVMs have no effective treatment. It is therefore important that newer treatment modalities are identified. A treatment that has shown some promise in cancer is vascular targeting. This method may provide an alternative treatment for AVMs without affecting surrounding normal brain vasculature. Previous work has identified phosphatidylserine (PS) as a potential target that is increased in the endothelium following radiation exposure. It is hypothesised that treatment of AVMs with gamma knife radiosurgery (GKS) and using a vascular targeting agent to deliver a pro-thrombotic compound can cause localised thrombosis and vessel occlusion within AVM vessels. Using a rat animal model, a novel vascular targeting conjugate was formed from the protein annexin V and thrombin to target PS. On assessment of the conjugate, AVM occlusion occurred in 75% of conjugate-treated animals with similar rates of flow cessation noted in the GKS and non GKS treated groups. These findings were noted both with angiographic occlusion and histological evidence of large and small vessel thrombus formation. On reducing the dose to half the dose per weight per animal and administering it in a multiple dose treatment regimen a statistically significant proportion of animals had evidence of AVM occlusion in only irradiated animals, suggesting effectiveness of sensitising AVMs with focussed irradiation. This research has demonstrated a significant association between use of the vascular targeting annex in V/ thrombin conjugate and thrombosis of AVM vessels both radiologically and histologically. This technique and the use of radiation sensitisation may demonstrate a potential new treatment for AVMs. This finding is the first of its kind in the treatment of AVMs and with further development may become an alternative treatment modality for previously untreatable lesions.1 online resource (231 pages) illustration