Abstract TMP33: TXA302 Promotes Permanent Functional Recovery With Delivery Initiated Up to 4 Weeks After Stroke in Multiple Rodent Models

Abstract

Introduction: TXA302 is a proprietary analogue of angiotensin 1-7 (Ang1-7). Previous studies have shown that intracerebroventricular administration of Ang1-7 as a pre-treatment to experimental occlusive rodent stroke resulted in improved neurological function, decreased infarct volume, enhanced cerebral blood flow and decreased inflammation. Here, systemic administration of TXA302 was evaluated with treatment delayed up to 4 weeks to assess the potential of TXA302 to promote recovery in chronic stroke. Methods and Results: Four independent studies were conducted in the rat transient (2 hour) and permanent middle cerebral artery occlusion (MCAO) models. Daily subcutaneous delivery of TXA302 or vehicle was started either 24 hours or 4 weeks after MCAO and continued for 4, 6 or 8 weeks. Treatment was started at 4 weeks to assess the ability of TXA302 to promote recovery independent of neuroprotection and to model the chronic phase of the injury. Two of the studies employed a dose range of TXA302 from 1 to 500 μg/kg and two studies had a washout period of 4 weeks after the completion of dosing to assess the permanence of the recovery effect. Sensorimotor recovery was measured by limb placing, stepping, and body swing tests along with composite neurological scoring. Cerebral blood flow (CBF) was evaluated by doppler ultrasonography. All studies were conducted in a blinded fashion and recovery of treated animals was compared to vehicle by repeated measures ANOVA with corrections for multiple comparisons. TXA302 treatment resulted in significant, robust and permanent dose-responsive improvements in neurological function and CBF compared to vehicle treated animals. Conclusions: The ability to delay treatment for 4 weeks suggests the changes are not attributable to neuroprotection. Furthermore, this wide therapeutic window enhances translational potential as clinical trials can be conducted without confounding factors of treating, stabilizing and assessing baseline functional measures in acute stroke patients. Ongoing studies are exploring the potential of TXA302 to enhance endogenous remodeling through angiogenesis and neural plasticity. Non-clinical studies and manufacturing development are underway to enable an IND for stroke recovery.