SBIR-STTR Award

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. 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. The microglial function is maintained in healthy brain and is pathogenically dysregulated in AD brain. The prominent genetic risk factors, 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 A? 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 validate the Xenon (Xe) gas ability to modulate microglia in AD mouse model and human, that will lead to development of novel AD treatment. 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 in acute and AD mouse models that Xe delivered through inhalation modulates brain microglia and preserve it in the hemostatic form. In this proposal we would like to further validate Xe action on microglia in-vivo in AD mice model and in neurogenerative human microglia. We will address our hypothesis in the following aims: Aim 1: Investigate whether Xe-gas treatment affects phenotype and function of neurodegenerative microglia in APP-PS1 mice. Aim 2: Validate whether Xe-gas treatment affects phenotype and function of neurodegenerative human microglia.Based on results of these work we will be able to develop the inhalation system and protocol for implementation of the therapeutic method for AD treatment. Public Health Relevance Statement Narrative Microglia, the primary immune cells and the sensor of the brain's health, play a pivotal role in the maintenance of brain homeostasis, but lose their functions during the course of aging and neurodegenerative diseases. The goal of this proposal is to develop treatment for protection neurons from apoptosis and microglia from acquiring neurodegenerative phenotype using noble gas xenon (Xe), which can ultimately become a novel AD therapy. We plan to investigate the protective effect of Xe on the AD brain homeostasis and design a method for Xe delivery in the optimal concentration.

Project Terms:
Affect ; Aging ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Anesthetics ; Anesthestic Drugs ; Anesthetic Agents ; Anesthetic Drugs ; Apolipoprotein E ; Apo-E ; ApoE ; Axon ; Biology ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Cells ; Cell Body ; Disease ; Disorder ; Equilibrium ; balance ; balance function ; Gases ; Noble Gases ; Group 18 Elements ; Inert Gases ; Rare Gases ; gas element ; Genes ; Goals ; Health ; Hemostatic Agents ; Hemostatics ; Homeostasis ; Autoregulation ; Physiological Homeostasis ; Human ; Modern Man ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Inhalation Device ; Maintenance ; Methods ; Transgenic Mice ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Legal patent ; Patents ; Patients ; Phagocytes ; Phagocytic Cell ; amebocyte ; Phagocytosis ; Phenotype ; Play ; Role ; social role ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Technology ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Transforming Growth Factor beta ; Bone-Derived Transforming Growth Factor ; Milk Growth Factor ; Platelet Transforming Growth Factor ; TGF B ; TGF-beta ; TGF-β ; TGFbeta ; TGFβ ; Transforming Growth Factor-Beta Family Gene ; Treatment Protocols ; Treatment Regimen ; Treatment Schedule ; Work ; Xenon ; Xe element ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; τ Proteins ; Mediating ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; base ; human subject ; sensor ; Acute ; repaired ; repair ; Microglia ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; Disease Progression ; Neuroprotective Agents ; Neuroprotectants ; Neuroprotective Drugs ; Brain Injuries ; Acquired brain injury ; brain damage ; brain-injured ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Collaborations ; muscle enhancer factor-2A ; MEF-2A ; MEF2A ; Therapeutic ; Genetic ; Inflammatory ; Amyloid Plaques ; Neuritic Plaques ; amyloid beta plaque ; amyloid-b plaque ; aβ plaques ; cored plaque ; diffuse plaque ; Senile Plaques ; tool ; programs ; Immunes ; Immune ; Protocol ; Protocols documentation ; Pattern ; System ; restoration ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; Ablation ; dimer ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; novel ; inherited factor ; genetic risk factor ; Regulation ; Network Analysis ; Pathway Analysis ; JV15-2 ; MADH3 ; Mothers Against Decapentaplegic, Drosophila, Homolog of, 3 ; SMA- and MAD-Related Protein 3 ; SMAD3 ; MADH3 gene ; Pathogenicity ; Address ; Data ; Molecular Fingerprinting ; molecular profile ; molecular signature ; Molecular Profiling ; in vivo ; Apoptotic ; Small Business Technology Transfer Research ; STTR ; Development ; developmental ; neuron apoptosis ; apoptosis of neuronal cells ; neuronal apoptosis ; neuronal cells programmed cell death ; neurons programmed cell death ; programmed cell death of neuronal cells by apoptosis ; programmed cell death of neurons by apoptosis ; APP-PS1 ; APP/PS1 ; design ; designing ; protective effect ; Cell model ; Cellular model ; Alzheimer like pathology ; Alzheimer's disease like pathology ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; neurodegenerative phenotype ; prototype ; brain health ; Inhalation ; Inhaling ; preservation ; Alzheimer's disease therapy ; Alzheimer's therapy ; Alzheimer's disease brain ; Alzheimer's brain ; therapeutically effective ;

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. Emerging evidenceshows 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 healthybrain and is pathogenically dysregulated in AD brain. The prominent genetic risk factor, APOE, is involved inmicroglial function. We have recently identified a unique molecular signature for homeostatic microglia and havedeveloped robust tools to investigate microglial biology in health and disease. We also identified a role for theAPOE-signaling in the regulation of a new microglial subset associated with neurodegeneration and in microgliasurrounding neuritic Ab-plaques in human AD brain, which we have termed MGnD. The major question relatesto microglia-based approach to treat AD is how to modulate microglia phenotype and function. Preservation ofneuronal cells from Aβ-induced apoptosis as well as restoration of resident microglial homeostatic function iscritical 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 inhealthy normal volunteers given at increasing durations of exposure: 20, 40, 60, and 90 minutes. Xe is currentlyused in human patients as an anesthetic and as a neuroprotectant in treatment of brain injuries. Xe penetratesblood brain barrier, which can make it effective therapeutic. Our preliminary data demonstrated that Xe deliveredthrough inhalation: 1) modulates microglia from an MGnD to homeostatic phenotype in an acuteneurodegeneration 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 inP301S 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 ofXe inhalation treatment in an acute model of neurodegeneration and in AD mice. Successful completion of thisclinical trial proposal will be the first step of evaluation of xenon inhalational therapy in humans and will allow tomove to its evaluation in AD patients for safety and efficacy, leading to raising private-sector capital and initiationof 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 durationsof exposure: 20, 40, 60, and 90 minutes.

Public Health Relevance Statement:
PHASE II APPLICATION (STTR Program PAS-22-197) Title: Phase 1 Trial to Assess Safety and Immune Effects of Xenon Gas in Healthy Human Subjects Narrative We showed that Xenon gas (Xe) delivered through inhalation suppresses neurodegenerative microglia and ameliorates Alzheimer's Disease (AD)-like pathology associated with decreased Ab-plaques in AD mouse models. The goal of this proposal is to perform Phase 1 dose-escalation safety study in healthy human subjects. This is the first clinical trial of Xe inhalation AD therapy in humans and its successful completion will allow initiation of safety and efficacy clinical trial in AD patients.

Project Terms: