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Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal)

Award Number: R01FD006071
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal) - Abstract Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. The genetic basis is an expansion of CTG repeats in the non-coding region of DMPK, the gene encoding DM protein kinase. Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias, and other symptoms. The disease mechanism involves a deleterious gain-of-function by the mutant DMPK mRNA, a process first described in DM1, known as RNA toxicity. RNA binding proteins become trapped on repetitive RNA, causing loss of splicing regulatory functions. Splicing changes contribute to DM1 symptoms and also may serve as biomarkers of disease severity. The discovery that DM1 is instigated by toxicity of one RNA species and characterized by misregulated splicing of other RNAs has furnished good therapeutic targets and candidate biomarkers. Several therapeutic approaches are under development and two are in early phase clinical trials. However, the design and conduct of clinical trials is limited by disease heterogeneity, scarcity of natural history data, and the lack of proven clinical endpoints or biomarkers of drug impact. We have begun a natural history study to define clinical endpoints, biomarkers, and patient characteristics for clinical trials. This study, END-DM1, has enrolled 277 participants but early progress was hampered by the COVID-19 pandemic. The current renewal application seeks to complete the study of clinical outcome assessments (Aim 1) and biomarkers (Aim 2) in DM1. We will complete enrollment of 700 adults with DM1 at 16 sites of the Myotonic Dystrophy Clinical Research Network with return visits at 12 and 24 months. Based on preliminary data, we selected a concise set of clinical measures showing acceptable reliability and responsivity to disease progression. The proposed study is designed to establish minimal clinically important differences for different measures in this population, identify baseline characteristics that predict future progression, and provide a rational basis for stratification, selection of sample size, or enrichment in future trials. Aim 2 will build on our previous efforts to develop RNA splicing biomarkers of DM1 severity and therapeutic response. This Aim is focused on tissue biomarkers that provide direct evidence of target engagement in skeletal muscle. We will assess a panel of DM1-affected splice events using a novel method that involves targeted high-throughput sequencing. Completion of this study is the logical next step to lay the groundwork for effective clinical trials in DM1, and keep pace with the rapidly expanding preclinical efforts to develop an effective drug treatment.


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 = $368,897 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	003	5	6/9/2025	NON-COMPETING CONTINUATION	$398,302
2025	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	001	3	2/24/2025	COMPETING CONTINUATION	$29,405
2025	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	000	2	2/24/2025	SUPPLEMENT FOR EXPANSION	-$29,405
2025	2017	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	002	2	5/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$29,405
														Subtotal = $368,897

Issue Date FY: 2024 ( Subtotal = $399,847 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	000	4	3/18/2024	NON-COMPETING CONTINUATION	$399,847
														Subtotal = $399,847

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	000	3	8/28/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $376,994 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	002	3	9/16/2022	COMPETING CONTINUATION	$386,995
2022	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	001	2	8/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2017	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Food and Drug Administration Research	000	1	6/21/2022	NEW	-$10,001
														Subtotal = $376,994

Issue Date FY: 2021 ( Subtotal = $98,005 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	001	2	9/29/2021	SUPPLEMENT FOR EXPANSION	$98,005
2021	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	000	2	9/17/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $98,005

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Food and Drug Administration Research	000	1	11/27/2018	NEW	-$1,961,707
2019	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Food and Drug Administration Research	001	2	11/29/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,961,707
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $1,988,003 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Food and Drug Administration Research	000	1	9/7/2017	NEW	$1,988,003
														Subtotal = $1,988,003

Grand Total All Awards = $3,231,746

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Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal)

Award Number: R01FD006071

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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