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Exploratory Therapy for the Skeletal/Dental Phenotype in PHOSPHO1 Deficiency

Award Number: R21DE031889
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: 03/11/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Exploratory Therapy for the Skeletal/Dental Phenotype in PHOSPHO1 Deficiency - Summary Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are two matrix vesicles (MVs)-associated enzymes critically important for the proper mineralization of skeletal and dental tissues. Inactivating mutations in the TNAP gene (ALPL in humans and Alp/ in mice) lead to hypophosphatasia (HPP) while ablation of the Phospho1 gene in mice leads to osteomalacia, fractures and early-onset scoliosis. The simultaneous ablation of Alp/ and Phospho1 lead to embryonic lethality characterized by complete absence of skeletal and dental mineralization. The significance of TNAP for biomineralization has been exploited therapeutically. Our laboratory has contributed much of the pre-clinical data validating mineral-targeted TNAP (asfotase alfa) for the treatment of HPP and approved in 2015 for pediatric-onset HPP. Since our demonstration that PHOSPHO1 deficiency in mice also leads to a soft bone phenotype not unlike HPP, a patient with PHOSPHO1 mutations displaying HPP like symptomatology has been identified. No treatment has yet been devised for this pseudo-HPP skeletal/dental disease and in this high-risk high-reward R21 application we propose to explore the potential therapeutic use of mineral-targeted TNAP to improve the skeletal and dental phenotype in our murine model of PHOSPHO1 deficiency.


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 = -$920 )
2025	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	2	6/18/2025	NON-COMPETING CONTINUATION	-$920
														Subtotal = -$920

Issue Date FY: 2023 ( Subtotal = $241,306 )
2023	2023	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	2	2/16/2023	NON-COMPETING CONTINUATION	$241,306
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	001	1	2/21/2023	NEW	$0
														Subtotal = $241,306

Issue Date FY: 2022 ( Subtotal = $309,319 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	1	3/11/2022	NEW	$309,319
														Subtotal = $309,319

Grand Total All Awards = $549,705

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Exploratory Therapy for the Skeletal/Dental Phenotype in PHOSPHO1 Deficiency

Award Number: R21DE031889

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: 03/11/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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