Monday, December 11, 2023 12/11/2023

Development of MRI, Alternative Splicing, and Functional Abilities asBiomarkers in Myotonic Dystrophy Type 1

Award Number: R01AR076060
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Myotonic Dystrophy Type 1 (DM1) is the most common form of muscular dystrophy in adults. It is caused by an unstable triple repeat of the myotonic dystrophy protein kinase (DMPK) gene. These repeats create retention of mutant mRNA in the nuclear foci causing alternative splicing abnormalities in many other genes and resultant multi-systemic pathology. The pathological muscular changes from DM1 cause progressive weakness, myotonia, gait impairments, decreased balance, increased fall risk, disability, and a shortened life span. Much progress has been made through preclinical studies to identify potential therapeutic targets to address the pathophysiology of DM1. However, the lack of sensitive, objective biomarkers is one of the largest obstacles in moving ahead with clinical trials. There is a dire need for repeatable and clinically relevant outcome measures to be developed so future studies can investigate new therapeutics. Both MRI and alternative splicing have been explored as biomarkers to assess skeletal muscle and disease pathology in DM1. While the initial results from preliminary studies have been promising, far greater detailed work remains to be completed in order to determine how these measures can be optimally used as clinically meaningful biomarkers for DM1 in support of the development of new therapies. Thus, the overall objective of this study is to validate quantitative MRI (qMRI) and alternative splicing as biomarkers in DM1. In Aim 1, 30 subjects with DM1 will be assessed with qMRI (from the upper and lower extremity musculature) and functional tests at baseline and at 18 months. The results will provide quantitative information about muscle pathology change over time and the clinical utility of qMRI. For Aim 2, these same 30 DM1 participants will have an MRI-Informed biopsy from which RNA will be isolated to quantitate splicing events. We will assess how alternative splicing is related to both qMRI and functional tests. Aim 3 will add alternative splicing data collection and analyses after 18 months to examine change over time in these events. We anticipate the results from this study will provide novel and vital information regarding the longitudinal changes in qMRI and alternative splicing as well as the relationships between qMRI, alternative splicing, and clinical assessments. This information will be key to the future use of these outcomes as biomarkers in future clinical trials for patients with DM1.


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: 2022 ( Subtotal = $205,917 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/15/2022	NON-COMPETING CONTINUATION	$205,917
														Subtotal = $205,917

Issue Date FY: 2021 ( Subtotal = $195,176 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/17/2021	NON-COMPETING CONTINUATION	$195,176
														Subtotal = $195,176

Issue Date FY: 2020 ( Subtotal = $182,137 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/4/2020	NEW	$0
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/17/2020	NEW	$182,137
														Subtotal = $182,137

Grand Total All Awards = $583,230

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Development of MRI, Alternative Splicing, and Functional Abilities asBiomarkers in Myotonic Dystrophy Type 1

Award Number: R01AR076060

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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