Recombinant ADAMTS13 Improves Neurological Outcome in Experimental Stroke in Mice.

Abstract 3134

Poster Board III-71

Ischemic stroke is a leading cause of death and disability and each year, about 795,000 people experience a new or recurrent stroke in the United States. The only FDA approved therapy available for stroke is tissue plasminogen activator (tPA), which converts inactive plasminogen into plasmin and then catalyzes the digestion of fibrin into soluble degradable products facilitating clot lysis. Although tPA was approved by the FDA, experiments in mice revealed side effects including increased risk of hemorrhage and induction of blood brain barrier breakdown. Therefore, there is a need for an alternative candidate drug. von Willebrand factor (VWF) is an adhesion molecule that plays an important role in platelet adhesion and cohesion at sites of vascular injury both at arterial and venous shear rates. The activity of VWF is modulated by ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) which cleaves VWF to smaller less active forms. Recently, it was demonstrated that deficiency of VWF protects mice from ischemic stroke in the middle cerebral artery occlusion model (MCAO) (Kleinschnitz et al., Blood, 2009.). This observation is in agreement with our previous findings presented at the 2008 ASH meeting. In addition, we have shown that deficiency of ADAMTS13 in mice aggravates consequences of ischemic stroke in the MCAO model. In this study, we evaluated the therapeutic potential of recombinant human ADAMTS13 (r-hu ADAMTS13) in prevention of stroke. We have previously shown that r-hu ADAMTS13 was effective in reducing platelet plug size in the ferric chloride arterial injury model in mice (Chauhan et al., JEM, 2006). We infused r-hu ADAMTS13 prior to reperfusion in wild-type (WT) mice that underwent one hour of middle cerebral artery occlusion. After 24 hours, WT mice infused with r-hu ADAMTS13 had approximately 30% smaller infarctions (P<0.05) compared to control (WT infused with vehicle). Additionally, we did not detect cerebral hemorrhage in the mice infused with r-hu ADAMTS13. To test whether the reduction in infarct volume actually improves functional outcome, we performed the tape removal test, a technique that assesses sensory and motor impairments in forepaw function. Twenty-four hours after surgery, mice that underwent one hour MCAO showed an increase in the time needed to remove adhesive tape from the contralateral and ipsilateral paws compared to sham-operated mice. Interestingly, treatment with r-hu ADAMTS13 significantly shortened the time to remove the adhesive tape when compared to vehicle treated mice (P < 0.05), indicating a profound improvement in sensorimotor performance of the r-hu ADAMTS13 treated mice. Taken together, these results show a protective role of ADAMTS13 and therapeutic effect of r-hu ADAMTS13 when infused after cerebral ischemia. Our findings suggest that recombinant ADAMTS13 could be considered as a new agent for prevention and/or treatment of stroke.