A Novel Xenon Delivery Platform for Cerebroprotection During Stroke

Project Summary/Abstract Stroke is a global health crisis, ranking as the second leading cause of death and disability worldwide. Stroke is estimated to cause over 6.5 million deaths and 143 million lost years of healthy life per annum. Occurring every 3 seconds on average, stroke is urgent and debilitating. It is a key contributor to long-term disability and ranks fifth in US mortality. Stroke arises from blocked or bleeding blood vessels in the brain, with about 87% being ischemic strokes. Building on successful Phase I and II STTR projects, this research explores a groundbreaking approach to stroke treatment. It involves intermittent administration of Xenon-Liposome (XKS07) for acute ischemic stroke (AIS). This strategy, inducing natural brain protection and extending reperfusion therapy's window, demonstrates multifaceted benefits including epigenetic-influences on long-term recovery. Zymo Research Corporation will partner with UTHealth as well as consultants at RTI and Contract Research Organization WuXi AppTec to carry out the research. The goal is to develop this formulation and strategy through IND-enabling studies for FDA pre- IND discussion and proceed to the IND application. Specific Aims are: Specific Aim 1 is to finish the validation of lead product in clinical translational models through SA 1a: Dose range finding (DRF) study; SA 1b: Identify and validate the Maximum effective dose (MaxED) in two clinically relevant stroke models; SA 1c: Develop and validate a physiologically based pharmacokinetic (PBPK) model for Xe dose allometric scaling. Once the lead product is validated, we will partner with the RTI Drug Development and Regulatory group for Specific Aim 2 to complete the FDA pre-IND briefing document and have a pre-IND meeting through SA 2a: Draft toxicology study protocol. SA 2b: Draft Phase 1 Clinical Trial protocol; and SA 2c: FDA pre-IND meeting to review and obtain feedback on the design of toxicology, product manufacture, and quality controls needed to initiate human studies. Once the pre- IND meeting is completed, we will conduct Specific Aim 3 for IND enabling, preparation, and filing through SA 3a: implement a quality management system for pharmaceutical cGMP production of XKS07; SA 3b: Complete GLP toxicology studies; we will work with RTI and WuXi AppTec on SA 3c: Prepare and file the IND with the FDA. Once the IND is approved, we will proceed to Phase I and II clinical trials. This project signifies a crucial step in addressing stroke management gaps and advancing cerebroprotection in acute stroke therapy.