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Treating T cell immunodeficiency among older adults by a recombinant Foxn1 fusion protein

Award Number: R33AG072234
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Treating T cell immunodeficiency among older adults by a recombinant Foxn1 fusion protein - Project Summary With modern advances in medicine, our average lifespan is increasing. However, advanced age is often accompanied by chronic diseases Our immune systems frequently plays a central role in the development of chronic diseases and T cells play a critical role in the immune system, providing protection against infection and cancer. The thymus, the primary organ for T cell development, however, undergoes a profound age-dependent atrophy, a process called thymic involution. Thymic involution results in T cell immunodeficiency, leading to increased susceptibility to infection and cancer, and difficulty in establishing protective immunity via vaccinations. Currently, there is no effective way to prevent or reverse T cell immunodeficiency among older adults. T cell development in the thymus is dependent on the thymic microenvironment, in which thymic epithelial cells (TECs) are the major components. However, TECs undergo qualitative and quantitative loss that is the major factor responsible for thymic atrophy. FOXN1 is a pivotal regulator for TEC development and maintenance, and we have shown that recombinant (r) FOXN1 fusion protein that contains FOXN1 and a protein transduction domain (PTD) can translocate from the cell surface into the cytoplasm and nucleus. Intrathymic (i.t.) injection of the rFOXN1 fusion protein into mice increases the number of TECs, and, consequently, enhances thymopoiesis and increases the number of T cells in the periphery. However, the i.t. injection route is impracticable for human application. Development of a more practicable regimen in term of the route of administration is necessary. The goal of this proposal is to develop new rFOXN1 fusion proteins that can migrate into the thymus to enhance thymopoiesis after intravenous (i.v.), intramuscular (i.m.), or subcutaneous (s.c.) injection into old mice. In the R21 phase, we will produce rFOXN1 fusion proteins containing FOXN1-PTD and thymus targeted peptides, or thymus/TEC specific receptor or antibody (Aim 1). We will then determine the ability of the rFOXN1 fusion proteins to migrate into the thymus when injected i.v., i.m. or s.c. (Aim 2), and to increase the number of TECs and T cells in old mice (Aim 3). If the R21 milestones are met, the R33 phase will be undertaken. Aim 4 will further characterize the thymus and the peripheral T cell function in the rFOXN1 fusion protein-treated old mice. In Aim 5, we will determine whether T cells in rFOXN1 fusion protein-treated old mice are immune tolerant to self-antigens to prevent autoimmunity. Aim 6 will analyze rodent toxicology and pharmacokinetics of a lead rFOXN1 fusion protein. Our long-term goal is to use the lead rFOXN1 fusion protein to prevent and treat T cell immunodeficiency in older adults, thus leading to improved healthcare outcomes and mortality rates.


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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	5	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $473,340 )
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	5	6/20/2025	NON-COMPETING CONTINUATION	$473,340
														Subtotal = $473,340

Issue Date FY: 2024 ( Subtotal = $628,923 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	001	4	5/24/2024	NON-COMPETING CONTINUATION	$483,000
2024	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	3	4/5/2024	EXTENSION WITH OR WITHOUT FUNDS	$145,923
														Subtotal = $628,923

Issue Date FY: 2023 ( Subtotal = $483,000 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	3	6/1/2023	EXTENSION WITH OR WITHOUT FUNDS	$483,000
														Subtotal = $483,000

Grand Total All Awards = $1,585,263

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Treating T cell immunodeficiency among older adults by a recombinant Foxn1 fusion protein

Award Number: R33AG072234

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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