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Phase 1 Trial to Assess Safety and Immune Effects of Xenon Gas in Healthy Human Subjects

Award Number: R42AG073059
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 10/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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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 Aβ-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $50,000 )
2025	2025	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	003	3	8/11/2025	SUPPLEMENT FOR EXPANSION	$50,000
2025	2024	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	002	3	4/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	004	3	8/13/2025	NON-COMPETING CONTINUATION	$0
2025	2024	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	000	3	12/17/2024	NON-COMPETING CONTINUATION	$0
2025	2023	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	001	2	4/11/2025	COMPETING CONTINUATION	$0
														Subtotal = $50,000

Issue Date FY: 2024 ( Subtotal = $1,181,599 )
2024	2024	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	001	3	8/29/2024	NON-COMPETING CONTINUATION	$1,181,555
2024	2023	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	000	2	12/4/2023	COMPETING CONTINUATION	$44
														Subtotal = $1,181,599

Issue Date FY: 2023 ( Subtotal = $1,318,445 )
2023	2023	GENERAL BIOPHYSICS LLC	13 RIDGEFIELD RD	WAYLAND	MA	01778	MIDDLESEX	USA	Aging Research	000	2	9/6/2023	COMPETING CONTINUATION	$1,318,445
														Subtotal = $1,318,445

Grand Total All Awards = $2,550,044

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Phase 1 Trial to Assess Safety and Immune Effects of Xenon Gas in Healthy Human Subjects

Award Number: R42AG073059

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 10/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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