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Local immunometabolism modulating biomaterials for immunosuppressive applications

Award Number: R01AR078343
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Local immunometabolism modulating biomaterials for immunosuppressive applications - Abstract Biomaterials-based strategies to modulate the immune responses has generated tremendous interest in the past decade. Notably, biomaterials can not only be used for delivering drugs (synthetic or biologics) but by themselves can modulate the function of different cells. Recently, we have demonstrated that the metabolite alpha-ketoglutarate (aKG) can be polymerized, and these polymers by themselves are able to suppress activation of dendritic cells (DCs – forms the bridge between innate and adaptive immune system). Interestingly, our preliminary data also demonstrates that delivery of PFK15, an inhibitor of PFKFB3 enzyme (a key step in glycolysis) downregulates CD86 (co-stimulatory molecule) but maintains MHC-II (stimulatory antigen presenting molecules) on DCs. Notably, glycolysis can control the function of activated DCs. Therefore, glycolysis-inhibition mediated prevention of DC activation and simultaneous antigen expression, can lead to antigen-specific immunosuppression responses. However, systemic inhibition of glycolysis has inherent toxicity (clinical trials) associated with it, and have regulatory hurdles for clinical use. Therefore, the main goal of this R01 program is to develop drug delivery vehicles that can deliver glycolysis inhibitors and antigens locally to DCs, which will then systemically suppress inflammation. The central hypothesis of this proposal is that co-delivery of antigen and glycolytic inhibitor will induce DC tolerance and generate peripheral antigen-specific suppressive T-cells, which will then promote reversal of tissue inflammation. This strategy will be tested in a rheumatoid arthritis animal model. This hypothesis will be tested by performing experiments in the following aims: AIM 1: Test if paKG formulations can generate long-term remission of RA by maintaining metabolic homeostasis in joint tissues. AIM 2: Determine the effect of paKG formulations on cells associated with arthritic tissue. AIM 3: Test the ability of paKG formulations to prevent progression of RA in K/BxN mice AIM 4: Develop scaled paKG formulations for safety/toxicity profiles. This research will be an important foundation in the development of technologies based on metabolic modulation of immune cells for autoimmune disorder treatment. The results from this project will generate a sustained release platform, which after application can prevent the progression of RA, or even reverse the damage.


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 = $303,855 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/17/2025	NON-COMPETING CONTINUATION	$303,855
														Subtotal = $303,855

Issue Date FY: 2024 ( Subtotal = $343,327 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,564
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	8/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,763
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	4	8/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$190,498
2024	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/11/2024	NON-COMPETING CONTINUATION	$0
2024	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	8/23/2024	NON-COMPETING CONTINUATION	-$190,498
														Subtotal = $343,327

Issue Date FY: 2023 ( Subtotal = $321,429 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/7/2023	NON-COMPETING CONTINUATION	$321,429
														Subtotal = $321,429

Issue Date FY: 2022 ( Subtotal = $319,920 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$29,085
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/28/2022	NON-COMPETING CONTINUATION	$290,835
														Subtotal = $319,920

Issue Date FY: 2021 ( Subtotal = $337,286 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/14/2021	NEW	$337,286
														Subtotal = $337,286

Grand Total All Awards = $1,625,817

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Local immunometabolism modulating biomaterials for immunosuppressive applications

Award Number: R01AR078343

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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