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Pharmacological inhibition of ENPP1 to promote cementum regeneration and periodontal return to function

Award Number: R21DE035696
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: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Pharmacological inhibition of ENPP1 to promote cementum regeneration and periodontal return to function - PROJECT SUMMARY/ABSTRACT Periodontal diseases are among the most prevalent on earth. Cementum is a root-covering mineralized periodontal tissue, which is critical for tooth attachment. Disorders that disrupt cementum formation or cause its destruction can result in periodontal ligament (PDL) detachment, periodontal dysfunction, and tooth loss. However, gaps in knowledge about factors that regulate cementum during development have, to date, limited therapeutic advances for cementum repair and regeneration. Inorganic pyrophosphate (PPi) is a physiological regulator of mineralization that works to prevent hydroxyapatite (HA) mineral growth. Modulation of PPi levels is a powerful approach to regulate cementogenesis. Through a series of experiments on human disorders, genetically engineered mouse models, and in vitro cell work, we established that PPi is perhaps the most important molecular regulator of cementum formation. Local levels of PPi are controlled by a few key proteins. Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) increases PPi levels, limiting mineralization. ENPP1 loss-of-function in development reduces PPi levels and dramatically increases cementum growth. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes and decreases PPi levels, promoting mineralization. Loss-of-function mutations in ALPL, which encodes TNAP, cause hypophosphatasia (HPP). HPP is a mineralization disorder that contributes to substantial dental mineralization defects, including loss of fully rooted deciduous and/or permanent teeth is pathognomic due to cementum defects. Limitations in the current HPP enzyme replacement therapy have prompted research into additional treatment strategies. Pharmacological targeting of ENPP1 function represents a promising alternative approach to reduce PPi in HPP and promote cementum growth, periodontal attachment, and tooth retention. Pilot studies using dietary administration of an ENPP1 inhibitor showed dramatic improvements in multiple skeletal defects in a mouse model of HPP. However, this therapeutic approach represents a much bigger opportunity where insights gained from studying a rare disease can more broadly impact oral health in the general population. The strategy to improve cementum in HPP can also be applied to periodontal disease, where cementum-PDL-alveolar bone structures must be regenerated to restore periodontal function. Our central hypothesis is that ENPP1 inhibition will improve cementum repair and periodontal function in models of HPP and periodontal disease. We will test this hypothesis by two aims: (1) Test pharmacological ENPP1 inhibition to ameliorate periodontal defects in a mouse model of HPP; (2) Define ability of pharmacological ENPP1 inhibition to re-establish cementum in a mouse model of periodontal regeneration. Expected outcomes of these proof-of-principle experiments include data to support future translational work employing ENPP1 inhibition to promote cementum repair, potentially scaling up to larger animal models and different models of periodontal disease.


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 = $469,207 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	1	1/27/2026	NEW	$469,207
														Subtotal = $469,207

Grand Total All Awards = $469,207

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Pharmacological inhibition of ENPP1 to promote cementum regeneration and periodontal return to function

Award Number: R21DE035696

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: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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