This project is focused on the development and validation of noninvasive biomarkers to characterize disease progression in Duchenne Muscular Dystrophy (DMD), Collagen VI related myopathies (Ullrich and Bethlem) and the Dysferiinopathies (LGMD2B/MM). Despite the poor prognosis of muscular dystrophy, therapeufic interventions have been lacking and outcome measures for clinical trials have been limited to measures of muscle funcfion and quality of life, serum biomarkers of muscle breakdown, and invasive muscle biopsies. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. Therefore, Project 3 will focus on magnetic resonance imaging (MRI) and spectroscopy (MRS) strategies to monitor pathophysiological features of dystrophy.
In Aim 1 a longitudinal MR natural history study will be implemented to evaluate the progressive involvement of the lower extremity muscles in three disfinct muscular dystrophy populations. In addifion, this aim will assess the relationship between alterafions in MR parameters and loss of muscle strength and funcfion.
Aim 2 is an exploratory aim that focuses on the development of novel MR strategies to quantify fibrosis in dystrophic skeletal muscle. State-of-the art sequences, such as ultra short echo and spectroscopic imaging, will be opfimized and tested in murine models of muscular dystrophy in Aim 2a.
Aim 2 b will rely on the development of a newly designed coil and opfimized pulse sequences to quantitafively map muscle fibrosis and intramuscular fat in subjects with muscular dystrophy using a clinical 3T system. Finally, a combinafion of cardiac MR techniques will be implemented to evaluate cardiac funcfion and progressive myocardial involvement in boys with DMD. We anticipate that the MR techniques opfimized and validated in this study will be appropriate for clinical trials in a wide range of muscular dystrophies.

Public Health Relevance

The goal of this project is to develop safe and noninvasive strategies to observe whether therapeutic intervenfions are effective in correcting the disease process in subjects with Duchenne Muscular Dystrophy, Collagen VI related myopathies and dysferiinopathies. This project focuses on both imaging of the leg muscles and the heart through the development of new technology

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR052646-07
Application #
8325180
Study Section
Special Emphasis Panel (ZNS1)
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$407,419
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Batra, Abhinandan; Harrington, Ann; Lott, Donovan J et al. (2018) Two-Year Longitudinal Changes in Lower Limb Strength and Its Relation to Loss in Function in a Large Cohort of Patients With Duchenne Muscular Dystrophy. Am J Phys Med Rehabil 97:734-740
Daniel, Bence; Nagy, Gergely; Czimmerer, Zsolt et al. (2018) The Nuclear Receptor PPAR? Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory. Immunity 49:615-626.e6
Willcocks, Rebecca J; Triplett, William T; Lott, Donovan J et al. (2018) Leg muscle MRI in identical twin boys with duchenne muscular dystrophy. Muscle Nerve :
Aartsma-Rus, Annemieke; Ferlini, Alessandra; McNally, Elizabeth M et al. (2018) 226th ENMC International Workshop:: Towards validated and qualified biomarkers for therapy development for Duchenne muscular dystrophy 20-22 January 2017, Heemskerk, The Netherlands. Neuromuscul Disord 28:77-86
Barthélémy, Florian; Defour, Aurélia; Lévy, Nicolas et al. (2018) Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet. J Neuromuscul Dis 5:21-28
Smith, Lucas R; Barton, Elisabeth R (2018) Regulation of fibrosis in muscular dystrophy. Matrix Biol 68-69:602-615
Hicks, Michael R; Hiserodt, Julia; Paras, Katrina et al. (2018) ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. Nat Cell Biol 20:46-57
Barnard, Alison M; Willcocks, Rebecca J; Finanger, Erika L et al. (2018) Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy. PLoS One 13:e0194283
Fallon, Justin R; McNally, Elizabeth M (2018) Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics. Matrix Biol 68-69:616-627
McNally, Elizabeth M; Wyatt, Eugene J (2017) Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. Circulation 136:979-981

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