O-027 Intra-arterial delivery of autologous mitochondria for ischemic stroke

Abstract

<h3></h3> Mitochondria are cellular powerhouses responsible for maintenance of homeostasis. Dysfunction of this cellular component has been associated with secondary injury after ischemic stroke. We postulated that autologous mitochondrial delivery via an intra-arterial route would mitigate injury caused by cerebral ischemia in a model resembling large vessel occlusion and revascularization. We used biochemical methods to purify autologous mitochondria from a single punch biopsy of skeletal muscle. The mitochondria were assayed for biological activity. Using mouse models of cerebral ischemia and reperfusion, we delivered viable mitochondria to ischemic brain parenchyma via an intra-arterial route. Using high-frequency focused ultrasound, we selectively opened the blood brain barrier over ischemic penumbra and assessed change in delivery of intra-arterial mitochondria and incorporation by various cell types. Using magnetic resonance imaging guided high-frequency ultrasound we assessed safety of selective blood brain barrier opening after cerebral ischemia. Purification of active mitochondria can be performed with minimal biochemical means within 15 minutes of a punch biopsy. The yield of mitochondria isolated is in the order of 10^9. Following delivery, mitochondria distribute through the stroked hemisphere and integrate into neural and glial cells in the brain parenchyma. Consistent with functional integration in the ischemic tissue, the transplanted mitochondria elevate concentration of adenosine triphosphate in the stroked hemisphere, reduce infarct volume and increase cell viability relative to controls. Mitochondria can be isolated in pure form in a clinically relevant time scale. The purified cellular components are biologically active. They can be readily administered intra-arterially into a stroke bed. The delivery of mitochondria can be enhanced via selective opening of the blood brain barrier using focused ultrasound. The mitochondria incorporate into cellular components of the central nervous system, thereby increasing viability. This represents a novel treatment strategy that can be combined with endovascular thrombectomy to aid in the improvement of outcomes after large vessel occlusion. <h3>Disclosures</h3> <b>Y. Kalani:</b> None. <b>P. Norat:</b> None. <b>P. Tvrdik:</b> None. <b>M. Levitt:</b> None. <b>M. Walker:</b> None.