Project Grant R42AG073059

PHASE 1 TRIAL TO ASSESS SAFETY AND IMMUNE EFFECTS OF XENON GAS IN HEALTHY HUMAN SUBJECTS - PHASE II APPLICATION (STTR PROGRAM PAS-22-197) "PHASE 1 TRIAL TO ASSESS SAFETY AND IMMUNE EFFECTS OF XENON GAS IN HEALTHY HUMAN SUBJECTS" ABSTRACT ALZHEIMER'S DISEASE (AD) IS ONE OF THE MOST PREVALENT NEURODEGENERATIVE DISORDERS. EMERGING EVIDENCE SHOWS THAT HOMEOSTATIC DYSREGULATION OF THE BRAIN IMMUNE SYSTEM, ESPECIALLY THAT ORCHESTRATED BY MICROGLIA, PLAYS A SIGNIFICANT ROLE IN THE ONSET AND PROGRESSION OF THE DISEASE. MICROGLIAL FUNCTION IS MAINTAINED IN HEALTHY BRAIN AND IS PATHOGENICALLY DYSREGULATED IN AD BRAIN. THE PROMINENT GENETIC RISK FACTOR, APOE, IS INVOLVED IN MICROGLIAL FUNCTION. WE HAVE RECENTLY IDENTIFIED A UNIQUE MOLECULAR SIGNATURE FOR HOMEOSTATIC MICROGLIA AND HAVE DEVELOPED ROBUST TOOLS TO INVESTIGATE MICROGLIAL BIOLOGY IN HEALTH AND DISEASE. WE ALSO IDENTIFIED A ROLE FOR THE APOE-SIGNALING IN THE REGULATION OF A NEW MICROGLIAL SUBSET ASSOCIATED WITH NEURODEGENERATION AND IN MICROGLIA SURROUNDING NEURITIC AB-PLAQUES IN HUMAN AD BRAIN, WHICH WE HAVE TERMED MGND. THE MAJOR QUESTION RELATES TO MICROGLIA-BASED APPROACH TO TREAT AD IS HOW TO MODULATE MICROGLIA PHENOTYPE AND FUNCTION. PRESERVATION OF NEURONAL CELLS FROM ASS-INDUCED APOPTOSIS AS WELL AS RESTORATION OF RESIDENT MICROGLIAL HOMEOSTATIC FUNCTION IS CRITICAL FOR THE RESTORATION OF BRAIN FUNCTION. THE GOAL OF THIS PROPOSAL IS TO PERFORM PHASE 1 CLINICAL TRIAL TO EVALUATE THE SAFETY OF XE INHALATION IN HEALTHY NORMAL VOLUNTEERS GIVEN AT INCREASING DURATIONS OF EXPOSURE: 20, 40, 60, AND 90 MINUTES. XE IS CURRENTLY USED IN HUMAN PATIENTS AS AN ANESTHETIC AND AS A NEUROPROTECTANT IN TREATMENT OF BRAIN INJURIES. XE PENETRATES BLOOD BRAIN BARRIER, WHICH CAN MAKE IT EFFECTIVE THERAPEUTIC. OUR PRELIMINARY DATA DEMONSTRATED THAT XE DELIVERED THROUGH INHALATION: 1) MODULATES MICROGLIA FROM AN MGND TO HOMEOSTATIC PHENOTYPE IN AN ACUTE NEURODEGENERATION MODEL AND IN AD MICE; 2) AMELIORATES AD-LIKE PATHOLOGY ASSOCIATED WITH DECREASED AB- PLAQUES IN APP/PS1 MICE; 3) REDUCES APOE4-INDUCED NEURODEGENERATION AND DECREASES BRAIN ATROPHY IN P301S MICE AND 4) DECREASES MONOCYTE INFILTRATION AND SUPPRESSES THEIR PROINFLAMMATORY RESPONSE. MECHANISTICALLY, WE FOUND THAT XE TREATMENT POLARIZES HOMEOSTATIC MICROGLIA TOWARD AN INTERMEDIATE STATE (MGIS), VIA INDUCTION OF MICROGLIAL RESPONSES TO IFNG SIGNALING. IMPORTANTLY, WE IDENTIFIED THE OPTIMAL PK/PD OF XE INHALATION TREATMENT IN AN ACUTE MODEL OF NEURODEGENERATION AND IN AD MICE. SUCCESSFUL COMPLETION OF THIS CLINICAL TRIAL PROPOSAL WILL BE THE FIRST STEP OF EVALUATION OF XENON INHALATIONAL THERAPY IN HUMANS AND WILL ALLOW TO MOVE TO ITS EVALUATION IN AD PATIENTS FOR SAFETY AND EFFICACY, LEADING TO RAISING PRIVATE-SECTOR CAPITAL AND INITIATION OF PHASE 2 CLINICAL TRIALS IN AD. THUS, WE PROPOSE THE FOLLOWING SPECIFIC AIM: AIM: TO EVALUATE THE SAFETY OF XE INHALATION IN HEALTHY NORMAL VOLUNTEERS GIVEN AT INCREASING DURATIONS OF EXPOSURE: 20, 40, 60, AND 90 MINUTES.