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Xenon gas treatment to modulate microglia in neurodegenerative diseases

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AG073059-01A1
Agency Tracking Number: R41AG073059
Amount: $813,098.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIA
Solicitation Number: PA20-272
Timeline
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-30
Award End Date (Contract End Date): 2023-02-28
Small Business Information
13 RIDGEFIELD ROAD
Wayland, MA 01778-4340
United States
DUNS: 080793244
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ILYA ILIN
 (617) 459-9088
 ilya.ilyin@generalbiophysics.com
Business Contact
 ILYA ILIN
Phone: (617) 459-9088
Email: ilya.ilyin@generalbiophysics.com
Research Institution
 BRIGHAM AND WOMEN'S HOSPITAL
 
75 FRANCIS STREET
BOSTON, MA 02115-6110
United States

 Domestic Nonprofit Research Organization
Abstract

Administrative Supplement Application PA-20-272
Xenon gas treatment to modulate microglia in neurodegenerative diseases (R41AG073059)
ABSTRACT
ABSTRACT FROM ORIGINAL APPLICATION
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 Aβ-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.
The goal of the original proposal was to investigate the Xenon (Xe) gas treatment to modulate microglia in AD
mouse models and human iPSCs-derived microglia transplanted in humanized AD mice. 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 original specific aims were as follow:
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.
SUPPLEMENTAL APPLICATION INFORMATION:
To make competitive Phase II application and transition to clinical trial, we are planning to hold a pre-IND meeting
with FDA. Developing such pre-IND meeting application was not a part of the original Phase I specific aims, but
is closely connected. This new administrative supplement request will increase the likelihood to achieve
additional critical Randamp;D milestones in the technology development pathway to make us more competitive for
Phase II application and ultimately for raising private-sector capital. The proposed scope of this additional
supplement is within the overall scientific scope of the parent grant, which we will be able to complete by end of
August 2022. The pre-IND submission package should include results of the originally proposed work and should
address the following new specific aims:
Aim 1: Determine PK/PD of Xenon inhalation treatment in an acute model of neurodegeneration and in
APP/PS1 mice. The primary goal of our current efforts is to translate Xenon technology for testing in human AD
patients. To prepare a competitive Phase II application for translation to humans, it is crucial to establish
parameters of dosing based on the PK/PD. In this Aim, we will determine PK/PD of Xenon inhalation treatment
in acute model of neurodegeneration and in AD mice.
Aim 2: Identify blood biomarkers in myeloid cells from healthy and AD patients to monitor Xenon
treatment. In this Aim, to monitor the efficacy of the Xe-treatment, we will determine the effect of Xenon
treatment on blood immune cells. The results of these new proposed experiments will establish blood biomarkers
for Xenon treatment and will be a crucial part for FDA submission and Phase I clinical trial.
Feasibility and timeframe: Considering our capabilities and already completed work, we believe that these new
important additional aims can be accomplished within the timeframe of the original grant and will take three
months. Importantly, the MGnD acute neurodegenerative model, which has been developed in our lab, can be
completed within 16hr. A new cohort of APP/PS1 mice has been generated, and the mice will be at 2 months of
age (early onset of disease) and will be ready to be tested for PK/PD (Aim 1). All human samples from HC and
AD patient are in hand (Aim 2).Narrative
Microglia, the primary immune cells and the sensor of the brainandapos;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.

* Information listed above is at the time of submission. *

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