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Targeting PTEN to ameliorate muscular dystrophy in a mouse model

Award Number: R01AR079235
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: 01/27/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Targeting PTEN to ameliorate muscular dystrophy in a mouse model - Targeting PTEN to ameliorate muscular dystrophy in a mouse model Abstract Duchenne muscular dystrophy (DMD) is a debilitating and lethal disease due to degeneration and wasting of skeletal muscles that are key for motility and respiration. Patients eventually lose ambulation and mobility, and experience respiratory failure. Currently there is no cure for this disease. The proposed research aims to provide basic understanding of how PTEN protein might be involved in the pathogenesis of DMD and explore a new PTEN-targeting therapeutic strategy to treat DMD in a mouse model, the mdx mice. The applicant’s team has recently identified phosphatase and tensin homolog (PTEN) as a new regulator of myogenesis. PTEN is a phosphatase that counteracts the growth factor-mediated signaling that is critical for muscle growth and repair through activation of muscle stem cells (also called muscle satellite cells, MuSCs). Interestingly, we and others found that PTEN levels are very low in healthy adult muscles but elevated in skeletal muscles of DMD patients and animal models, suggesting that PTEN upregulation may contribute to disease progression. To confirm this, we show in preliminary studies that muscle-specific knockout of Pten gene ameliorates muscle pathology and restores muscle function in mdx mice. These exciting results confirm that inhibition of PTEN may be translated to treat DMD in humans. However, targeting PTEN and its signaling requires a thorough understanding of the cellular and molecular mechanisms underlying PTEN function in dystrophic muscle, which will be investigated in the first part of the proposed study. To further explore the translatability of this discovery, we tested in preliminary studies the effect of a pharmacological inhibitor of PTEN (namely VO-OHpic) in mdx mice. We showed that VO-OHpic robustly improves muscle health and function without obvious side effects. To further improve the safety of VO-OHpic in vivo, we generated a nanoparticle (NP)-mediated delivery system with which to deliver VO-OHpic specifically to muscle cells to achieve sustained drug release and limit side effects. In the second part of the proposed research, we will further optimize this prototype drug delivery system and examine its utility and safety in mdx mice. Upon completion of the study, we will have not only gained imperative insights into the pathological function of PTEN in dystrophic muscle, but also developed a novel drug delivery system for sustained pharmacological inhibition of PTEN specifically in the muscle to ameliorate muscle pathology and improve muscle function in a preclinical animal model. These results will establish a solid foundation for clinical translation of this promising therapeutic strategy to treat DMD in humans. The muscle-targeting NP drug delivery system may also be adapted to deliver other therapeutics to treat DMD or other degenerative diseases.


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 = $319,770 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	3/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,770
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	4	6/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$554,822
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/20/2025	NON-COMPETING CONTINUATION	$0
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	3	6/10/2025	NON-COMPETING CONTINUATION	-$323,080
2025	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	6/10/2025	NON-COMPETING CONTINUATION	-$231,742
														Subtotal = $319,770

Issue Date FY: 2024 ( Subtotal = $323,080 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/29/2024	NON-COMPETING CONTINUATION	$23,315
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/28/2023	NON-COMPETING CONTINUATION	$299,765
														Subtotal = $323,080

Issue Date FY: 2023 ( Subtotal = $333,072 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$299,765
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/23/2023	NON-COMPETING CONTINUATION	$33,307
														Subtotal = $333,072

Issue Date FY: 2022 ( Subtotal = $333,072 )
2022	2022	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/27/2022	NEW	$333,072
														Subtotal = $333,072

Grand Total All Awards = $1,308,994

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Targeting PTEN to ameliorate muscular dystrophy in a mouse model

Award Number: R01AR079235

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: 01/27/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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