Tuesday, May 13, 2025 5/13/2025

Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells

Award Number: R01AR077435
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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Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells - Abstract Low back pain is the leading cause of disability in the United States, with an estimated socioeconomic cost exceeding $100 billion each year. Intervertebral disc degeneration, a cascade of cellular, compositional, structural and compositional changes, is strongly implicated as a cause of low back pain. Current clinical approaches for treating low back pain associated with disc degeneration have limited long term efficacy as they seek only to manage symptoms without restoring native disc structure and mechanical function. There is an overwhelming clinical need for new treatment options, which target not only the symptoms of low back pain, but also the underlying causes. Mesenchymal stem cells (MSCs) are an attractive option for cell- based disc regeneration due to their safety, ease of isolation and ability to adopt phenotypes similar to those of disc nucleus pulposus cells. A major challenge to successful MSC-based disc regeneration, however, is the local cellular microenvironment, which presents conditions of limited nutrition, low oxygen, low pH, and persistent inflammation that predispose therapeutic interventions to failure. The objective of this proposal is to develop a novel biological therapy that maximizes the survival and anabolic potential of therapeutic stem cells by simultaneously neutralizing the degenerate disc microenvironment via the sustained delivery of nutrients, anti-inflammatory drugs and buffering agents. To accomplish this goal, we will leverage our newly established goat model of disc degeneration that mimics clinically relevant structural, composition and biomechanical characteristics, including tissue-level inflammation, and novel drug delivery methods to enable controlled and sustained release of biofactors that neutralize the degenerative microenvironment. In Aim 1 we will leverage our goat model define the in vivo cellular microenvironment of the disc as a function of degeneration severity, using cutting edge in situ physiological monitoring and ex vivo biomolecular assays. In Aim 2 we will optimize our novel microcapsule drug delivery system to neutralize the degenerate disc microenvironment through sustained delivery of glucose, anti- inflammatory drugs and buffering agents. In Aim 3 we will carry out short and long term in vivo studies to establish therapeutic efficacy in our goat model, including clinically-relevant pain assessments. At the conclusion of these studies we will have developed a rapidly translatable therapy that maximizes the regenerative potential of MSCs in the disc microenvironment, and established long term preclinical efficacy, thus placing us in a strong position to move towards human clinical trials.


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 = $500,264 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/3/2025	NON-COMPETING CONTINUATION	$500,264
														Subtotal = $500,264

Issue Date FY: 2024 ( Subtotal = $546,109 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/5/2024	NON-COMPETING CONTINUATION	$39,410
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/29/2023	NON-COMPETING CONTINUATION	$506,699
														Subtotal = $546,109

Issue Date FY: 2023 ( Subtotal = $537,934 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	2/16/2023	NON-COMPETING CONTINUATION	$53,793
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/11/2023	NON-COMPETING CONTINUATION	$484,141
														Subtotal = $537,934

Issue Date FY: 2022 ( Subtotal = $545,884 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/8/2021	NON-COMPETING CONTINUATION	$496,258
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/9/2022	NON-COMPETING CONTINUATION	$49,626
														Subtotal = $545,884

Issue Date FY: 2021 ( Subtotal = $587,313 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/1/2021	NEW	$587,313
														Subtotal = $587,313

Grand Total All Awards = $2,717,504

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Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells

Award Number: R01AR077435

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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