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Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum

Award Number: R01AR075867
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum - Abstract Ectopic calcification represents a pathologic process characterized by mineralization of soft tissues. Pseudoxanthoma Elasticum (PXE) is an autosomal recessive genetic disorder characterized by progressive ectopic calcification of the eyes, skin heart and blood vessels and associated with devastating clinical sequelae such as blindness, sudden death and skin problems such as poor wound healing. PXE is an orphan disease and though ABCC6 has been identified as the causative gene, there currently do not exist any therapies for PXE. In this application we identify a novel molecular target, ENPP1 (ectonucleotide-pyrophosphatase 1) as a critical mediator of calcification in PXE. We demonstrate that ENPP1 is dramatically upregulated in calcific tissues in PXE and alters the pyrophosphate/phosphate balance to create a permissive environment for calcification to occur. We have created small molecules and monoclonal antibodies targeting ENPP1 and demonstrate the role of these agents in preventing calcification in PXE. Using murine models of PXE along with human pluripotent stem cell modeling of PXE, we investigate the molecular and biochemical role of ENPP1-PPi-Pi axis in mediating calcification in PXE and identify novel pharmacologic agents for the treatment of this incurable disorder. If successful, our proposal may lead directly to the identification of novel therapeutic strategies for PXE.


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 = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $343,200 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/10/2023	NON-COMPETING CONTINUATION	$34,320
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/13/2022	NON-COMPETING CONTINUATION	$308,880
														Subtotal = $343,200

Issue Date FY: 2022 ( Subtotal = $339,768 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/6/2021	NON-COMPETING CONTINUATION	$308,880
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/11/2022	NON-COMPETING CONTINUATION	$30,888
														Subtotal = $339,768

Issue Date FY: 2021 ( Subtotal = $332,904 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/18/2021	NON-COMPETING CONTINUATION	$24,024
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/2/2020	NON-COMPETING CONTINUATION	$308,880
														Subtotal = $332,904

Issue Date FY: 2020 ( Subtotal = $343,200 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/31/2020	NEW	$343,200
														Subtotal = $343,200

Grand Total All Awards = $1,359,072

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Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum

Award Number: R01AR075867

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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