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Treatment for Medication-related Osteonecrosis of the Jaw in Rice Rats via In Situ Delivery of an Anti-Inflammatory Enzyme with Spatial Metabolome/Glycome Profiling of Disease Progression and Therapy

Award Number: R21DE035645
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/09/2026
PERIOD OF PERFORMANCE END DATE: 07/08/2028

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Treatment for Medication-related Osteonecrosis of the Jaw in Rice Rats via In Situ Delivery of an Anti-Inflammatory Enzyme with Spatial Metabolome/Glycome Profiling of Disease Progression and Therapy - Project Summary Medication-related osteonecrosis of the jaw (MRONJ) is a serious condition defined by exposed, necrotic jawbone. It primarily affects cancer patients on bone-modifying drugs (like the bisphosphonate zoledronic acid [ZOL]), who also suffer oral diseases (e.g., periodontitis [PD]) or tooth extractions. Despite progress in understanding this condition, it remains a major clinical challenge. Inflammation is central to MRONJ formation. Strong evidence indicates that although bisphosphonates reduce bone metastases, they also intensify inflammation, thereby promoting MRONJ. Our team aims to develop a new strategy for preventing MRONJ and inducing healing. Metabolic reprogramming, which alters endogenous cell endproducts, provides a novel approach for suppressing inflammation. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that produces anti- inflammatory KYN metabolites. Galectin-3 (Gal-3), a sugar-binding protein, enhances the effectiveness of IDO by maintaining its localization in tissues. Our team engineered an IDO-Gal3 fusion protein that has previously been effective in suppressing inflammation in models of PD, osteoarthritis, and psoriasis. Using a rice rat model that mimics human MRONJ, pilot data showed that a single dose of IDO-Gal3 prevented MRONJ in ZOL-treated rice rats with PD. In contrast, all untreated controls developed it, providing strong support for further studies. We propose the hypothesis that local IDO-Gal3 delivery will reduce MRONJ prevalence and modulate the local metabolic and glycomic profiles towards healthy levels. The study will have 2 specific aims: Aim 1: Determine effects of local IDO-Gal3 delivery during MRONJ development in rice rats. PD rats treated with ZOL will be injected with IDO-Gal3 (single or repeated doses) or vehicle into the PD lesion, while controls receive a placebo. We will monitor rats using advanced imaging techniques. We will then examine the jaw tissues to determine MRONJ prevalence, severity, and degree of inflammation associated with MRONJ, as well as markers of cell death. We expect IDO-Gal3-treated rats to have a lower prevalence of MRONJ and less severe lesions compared to control rats. Aim 2: Identify spatial metabolome/glycome profiles of the MRONJ prodrome with or without IDO-Gal3 therapy. Working hypothesis: IDO-Gal3 modulates inflammation by locally increasing anti-inflammatory metabolites and decreasing pro-inflammatory metabolites, as well as correcting inflammation-induced extracellular matrix/cell- surface glycan alterations. Rats with PD treated with ZOL will receive IDO-Gal3 or vehicle, and jaw tissues will be collected at defined intervals for advanced metabolomic and glycomic profiling analyses to identify lesion- specific changes. Confirming our hypothesis will demonstrate advances in fundamental knowledge for creating MRONJ prevention strategies, the translational potential of IDO-Gal3 delivery, and lay the groundwork for future therapies and early diagnostic biomarkers.


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 = $428,188 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	1	7/14/2026	NEW	$428,188
														Subtotal = $428,188

Grand Total All Awards = $428,188

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Treatment for Medication-related Osteonecrosis of the Jaw in Rice Rats via In Situ Delivery of an Anti-Inflammatory Enzyme with Spatial Metabolome/Glycome Profiling of Disease Progression and Therapy

Award Number: R21DE035645

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/09/2026

PERIOD OF PERFORMANCE END DATE: 07/08/2028

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