Thursday, November 21, 2024 11/21/2024

Improved Tools for Accessing Pain Following Fracture and Enabling Standardized Pain Phenotyping

Award Number: R01AR077761
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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ABSTRACT The long-term goal of this project is to develop and validate an injectable, biodegradable nanowire delivery platform for local and sustained release of a “painless” nerve growth factor (NGF) isoform to accelerate fracture healing in clinical scenarios of delayed healing. Approximately 15 million fracture injuries occur each year in the United States (US).6 An estimated 10-15% of fractures within a healthy population result in delayed- or non-union.7,8 However, delayed healing rates increase to almost 50% in patients with vascular damage or high co-morbidity burdens such as diabetes, increased age, smoking, and obesity.9,10 The current standard of care for delayed healing or non-union is surgical intervention to increase stability or to promote healing through application of bone grafts. Bone morphogenetic protein (BMP) is the only biologic with FDA approval for use in fracture repair, with “on-label” use only within a narrow indication window. However, BMP requires surgical implantation and is typically limited to only the most at-risk fractures due to the high cost, limited evidence of clinical efficacy, and risk of severe off-target effects.11-14 As such, there exists an unmet clinical need for biologics that could stimulate bone regeneration in a non-surgical delivery platform. This application builds on strong preliminary data demonstrating that NGF accelerates fracture repair when injected into the cartilaginous phase of long bone healing. Importantly, our preliminary data is the first to show that NGF acts on chondrocytes to promote programs associated with endochondral ossification (EO). The goal of this grant is to build upon these preliminary data to develop NGF into a platform suitable for clinical translation. In the first Aim, we optimize the dose and timing of a mutant form of NGF (NGFR100W) to stimulate endochondral fracture repair. NGFR100W is a novel “painless” NGF that efficiently binds to the TrkA receptor to provide the same trophic effect as wild type NGF, but fails to bind to the p75NTR receptor to significantly reduce risk of nociception.15,16 In the second Aim, we probe the mechanism by which NGF/NGFR100W stimulates fracture repair by conditionally deleting the TrkA receptor. To date the molecular pathways stimulated by therapeutic delivery of NGF have not been rigorously studied in long bone fracture healing. Lastly, in the third Aim, we modify our previously developed injectable heparin coated polycaprolactone (PCL) nanowires17 for encapsulation and sustained delivery of painless NGF. Here we also incorporate a pre-clinical model of diabetes (Lepob) established to demonstrate delayed healing to challenge our therapy in a clinically relevant scenario of malunion. These aims allow us to test the central hypothesis that a painless NGF therapy can improve fracture healing by acting through TrkA signaling to stimulate chondrocyte-to-osteoblast transformation. Our interdisciplinary team of experts in fracture healing, biomaterials, and NGF/TrkA signaling uniquely positions us to successfully accomplish the proposed study. Importantly, our approach is grounded in creating a translationally relevant therapeutic platform that has the potential to significantly improve patient outcomes following a fracture.


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 = $660,093 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	11/7/2024	SUPPLEMENT FOR EXPANSION	$48,042
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$612,051
														Subtotal = $660,093

Issue Date FY: 2023 ( Subtotal = $1,019,890 )
2023	2023	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 W MEADOW DR STE 1000	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	8/21/2023	SUPPLEMENT FOR EXPANSION	$47,393
2023	2023	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 W MEADOW DR STE 1000	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	9/1/2023	SUPPLEMENT FOR EXPANSION	$516,399
2023	2023	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 W MEADOW DR STE 1000	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/12/2023	NON-COMPETING CONTINUATION	$456,098
														Subtotal = $1,019,890

Issue Date FY: 2022 ( Subtotal = $475,255 )
2022	2022	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 WEST MEADOW DRIVE	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/20/2022	SUPPLEMENT FOR EXPANSION	$43,428
2022	2022	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 WEST MEADOW DRIVE	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	7/8/2022	NON-COMPETING CONTINUATION	$431,827
2022	2021	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 WEST MEADOW DRIVE	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/3/2022	NEW	$0
														Subtotal = $475,255

Issue Date FY: 2021 ( Subtotal = $482,568 )
2021	2021	STEADMAN PHILIPPON RESEARCH INSTITUTE	181 WEST MEADOW DRIVE	VAIL	CO	81657	EAGLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/21/2021	NEW	$482,568
														Subtotal = $482,568

Grand Total All Awards = $2,637,806

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Improved Tools for Accessing Pain Following Fracture and Enabling Standardized Pain Phenotyping

Award Number: R01AR077761

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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