Project 2: Muscular dystrophy clinical trial foundations. Substantial evidence implicates aberrant reactivation of DUX4 expression as the cause of facioscapulohumeral dystrophy (FSHD). Expression profiling of primary myoblasts transduced with DUX4 has identified DUX4 regulated genes, many of which are involved in germline and early stem cell development. Many of these genes are expressed in FSHD muscle but not in muscle from healthy controls, making them ideal biomarker candidates. As FSHD research enters a translational phase, the development of mechanistic, prognostic, and diagnostic biomarkers becomes critical in moving the translational process forward.
Aim 1 is a cooperative clinical study for biomarker evaluation in FSHD that will (a) develop FSHD patient registration, assessments, and sample collection in Seattle that parallel those developed in Rochester;(b) develop FSHD MRI assessment capabilities in Rochester that parallel those developed in Seattle;and (c) perform a focused collaborative clinical study to determine the molecular determinants of the MRI findings characteristic of FSHD and to prioritize the best candidate biomarkers for disease activity.
Aim 2 will determine whether CD8+ T cells infiltrating FSHD muscle recognize DUX4 induced cancer/testes (C/T) antigens, and will (a) characterize the phenotype, location, and cytokine profile of the T cell/immune cell infiltrate in skeletal muscle in FSHD;(b) expand T cells from FSHD muscle, determine the T cell receptor Vb gene usage and characterize their function;and (c) determine whether T cells derived from FSHD muscle recognize FSHD muscle antigens. These combined aims represent a synergistic effort to evaluate the relationship between tissue biomarkers, histopathology, MRI imaging characteristics, and muscle function, together with a direct characterization of the T cell infiltrate the immune response in the pathophysiology of FSHD.
This project relates to the broad scope of the Center because it develops the clinical infrastructure necessary for future gene therapy trials in Duchenne and FSHD dystrophies at the University of Washington, and for future inter-institutional trials in muscular dystrophies. In addition it provides a rich translational clinical research program for the Investigator Development and Patient Outreach Core and it uses vectors produced by the Scientific Research Resource Core
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|Adams, Marvin E; Odom, Guy L; Kim, Min Jeong et al. (2018) Syntrophin binds directly to multiple spectrin-like repeats in dystrophin and mediates binding of nNOS to repeats 16-17. Hum Mol Genet 27:2978-2985|
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|Bengtsson, Niclas E; Hall, John K; Odom, Guy L et al. (2017) Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun 8:14454|
|Amoasii, Leonela; Long, Chengzu; Li, Hui et al. (2017) Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci Transl Med 9:|
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|Elverman, Matthew; Goddard, Melissa A; Mack, David et al. (2017) Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve 56:943-953|
|Whitehead, Nicholas P; Bible, Kenneth L; Kim, Min Jeong et al. (2016) Validation of ultrasonography for non-invasive assessment of diaphragm function in muscular dystrophy. J Physiol 594:7215-7227|
|Kolwicz Jr, Stephen C; Odom, Guy L; Nowakowski, Sarah G et al. (2016) AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility. Mol Ther 24:240-250|
|Statland, Jeffrey M; Tawil, Rabi (2016) Facioscapulohumeral Muscular Dystrophy. Continuum (Minneap Minn) 22:1916-1931|
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