Clinical Trials and Biomarkers of Myostatin Inhibition

Project 1 - Principal Investigator: Kathryn R. Wagner

FSHD is one of the most common forms of muscular dystrophy across populations. The progressive loss of skeletal muscle strength in FSHD causes patients to lose physical function and quality of life. Despite this heavy public health burden, there has been a paucity of clinical trials in FSHD, and no effective therapeutic agents have been identified or developed for FSHD. Our Wellstone center is pursuing clinical trial development with multiple pharmaceutical companies. Project 1 concentrates on the development of biomarkers that would facilitate upcoming trials in FSHD. We have recently identified several molecular biomarkers of myostatin inhibition which we published in Physiol. Genomics April 2011; 43(8):398-407. Work continues on characterizing novel pathways identified from this work for the purpose of not only understanding myostatin biology but for following myostatin inhibition in a clinical trial setting. The other major goal of Project 1 is to combine new techniques in MR imaging and spectroscopy to identify quantitative muscle markers in Facioscapulohumeral muscular dystrophy (FSHD). We are comparing and correlate these markers to the current standard outcome measures in muscle disease (biopsy studies and muscle strength testing) to develop a novel imaging methodology that can be used as a surrogate outcome measure in clinical trials of FSHD and other muscle diseases. This aim is integrated with, and take advantage of Core C, using the same subjects recruited for the biopsy program to provide imaging data prior to muscle biopsy. Imaging studies underway include a cross-sectional MRI and MRS study of 30 subjects with genetically-confirmed FSHD and a comparison of MRI and MRS profiles of subjects with FSHD to groups of healthy and diseased controls. Correlations between imaging biomarkers and molecular/histological biomarkers are being studied. Finally, Project 1 seeks to verify and better characterize disease-specific metabolic profiles in FSHD and controls using ultra-high magnetic resonance techniques. One of the significant limitations of MRS at present is low spatial resolution compared to other imaging modalities. One way to address this limitation is by increasing the applied magnetic field strength. At ultra-high fields, a higher signal-to-noise ratio results in improved spatial resolution on anatomic imaging and greater resolution of metabolic peaks on spectroscopy. This in turn will allow us to be more precise in our measurements of metabolite concentration and may even identify new compounds that can serve as biomarkers. In this specific aim, we will adapt the 3T skeletal muscle MRS protocol to the 7 Tesla (7T) magnet. The expected product of this research endeavor is a muscle imaging protocol that will be able to quantitatively and non-invasively assess disease severity and progression or regeneration in FSHD. This will include both morphologic imaging and spectroscopic parameters that can be repeated in a longitudinal fashion. We anticipate subsequently validating this protocol in a clinical trial in subjects with FSHD.


Kathryn Wagner, M.D., Ph.D.
Center for Genetic Muscle Disorders
The Kennedy Krieger Institute
Associate Professor
Department Neurology and Neuroscience
The Johns Hopkins School of Medicine
707 North Broadway, Room 400A
Baltimore, MD 21205 USA
(443) 923-9525
(443) 923-9545 fax

Louis Kunkel, Ph.D.
Enders 5
Children's Hospital
300 Longwood Avenue
Boston, MA 02115 USA
(617) 355-8200 or (617) 355-6729
(617) 730-0253 fax