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Three-model platform for understanding DMD epigenetic mechanisms and advancing small molecule therapies

Award Number: R01AR076978
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: 02/04/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Three-model platform for understanding DMD epigenetic mechanisms and advancing small molecule therapies - PROJECT SUMMARY Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. The current standard of care, corticosteroid treatment, delays the progression of muscle dysfunction but has serious side effects. DMD gene therapy and gene editing approaches are promising but face many challenges. Pharmacological approaches are being identified that could benefit DMD by modulating pathological mechanisms independent of the dystrophin mutation. However, many small molecule therapies have had difficulties showing efficacy while progressing through DMD clinical trials, possibly due to inadequate preclinical evaluation or to targeting mechanisms too late in the disease process. Although DMD is a progressive disease, there is evidence for early, embryonic- and fetal-stage defects in myogenesis and gene expression in DMD. In particular, our preliminary studies have identified one of the earliest known DMD phenotypes: a novel transcriptional trajectory of DMD human induced pluripotent stem cells (hiPSCs) undergoing myogenesis. By understanding how these early myogenic and transcriptional defects initiate and how they drive DMD pathology, we may be better positioned to identify and utilize DMD therapies. The hypothesis of this proposal is that epigenetic drugs, small molecules that target chromatin modifications and transcriptional regulation, can ameliorate early DMD transcriptional defects as well as improve downstream DMD pathology. Certain histone deacetylase inhibitors (HDACi) have shown promise for DMD in mice, zebrafish, and recent clinical trials. However, beyond these HDACi, epigenetic drugs have not been broadly and systematically studied for their efficacy and safety to treat DMD. The goals of this proposal are to identify novel epigenetic small molecules that are beneficial for DMD, by demonstrating effectiveness in multiple DMD models, and, in parallel, to better characterize the disrupted transcriptional and epigenetic mechanisms underlying DMD. We propose three Aims. First, we will identify the classes of epigenetic small molecules that improve the DMD phenotype, by screening an epigenetic drug library in dmd zebrafish. Our preliminary studies have already identified novel epigenetic drugs that rescue dmd zebrafish. Second, through single-cell genomics on hiPSC-derived DMD skeletal muscle, we will generate maps of transcriptome and chromatin packaging defects during the initiation and progression of DMD. We will test whether epigenetic drugs correct the novel transcriptional dysregulation phenotype, as well as functional deficits, that we have identified in hiPSC-derived DMD muscle. Third, we will evaluate epigenetic drugs for efficacy and safety in the DMD rat, assessing clinically relevant functional outcomes in skeletal and cardiac muscle. This project will provide novel basic scientific insight into the early epigenetic dysregulation occurring in DMD. The long-term impact will be the development of a three-model platform, zebrafish, rat and hiPSC lines, for DMD drug discovery and mechanistic and functional validation, taking advantage of each model system.


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 = $528,922 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	4/30/2025	NON-COMPETING CONTINUATION	$38,170
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/20/2024	NON-COMPETING CONTINUATION	$490,752
														Subtotal = $528,922

Issue Date FY: 2024 ( Subtotal = $528,922 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/5/2024	NON-COMPETING CONTINUATION	$38,170
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/4/2023	NON-COMPETING CONTINUATION	$490,752
														Subtotal = $528,922

Issue Date FY: 2023 ( Subtotal = $550,002 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	4/20/2023	NON-COMPETING CONTINUATION	$55,001
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$495,001
														Subtotal = $550,002

Issue Date FY: 2022 ( Subtotal = $571,121 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/22/2022	NON-COMPETING CONTINUATION	$519,200
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/25/2022	NON-COMPETING CONTINUATION	$51,921
														Subtotal = $571,121

Issue Date FY: 2021 ( Subtotal = $546,971 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/4/2021	NEW	$546,971
														Subtotal = $546,971

Grand Total All Awards = $2,725,938

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Three-model platform for understanding DMD epigenetic mechanisms and advancing small molecule therapies

Award Number: R01AR076978

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: 02/04/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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