Electrophysiological biomarkers in spinal muscular atrophy: proof of concept
Article first published online: 6 DEC 2013
© 2013 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
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Annals of Clinical and Translational Neurology
Volume 1, Issue 1, pages 34–44, January 2014
How to Cite
David Arnold, W., Porensky, P. N., McGovern, V. L., Iyer, C. C., Duque, S., Li, X., Meyer, K., Schmelzer, L., Kaspar, B. K., Kolb, S. J., Kissel, J. T. and Burghes, A. H. M. (2014), Electrophysiological biomarkers in spinal muscular atrophy: proof of concept. Annals of Clinical and Translational Neurology, 1: 34–44. doi: 10.1002/acn3.23
- Issue published online: 22 JAN 2014
- Article first published online: 6 DEC 2013
- Manuscript Accepted: 12 NOV 2013
- Manuscript Revised: 9 NOV 2013
- Manuscript Received: 13 SEP 2013
- NIH. Grant Numbers: 5K12HD001097-17, HD006508
- Swiss National Science Foundation
- NIH/NINDS. Grant Numbers: U01NS080836, K08NS067282, U01NS079163
Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model.
Sciatic CMAP, MUNE, and EMG were obtained in SMN∆7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMN∆7 mice treated with antisense oligonucleotide (ASO) or gene therapy.
CMAP was significantly reduced in SMN∆7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMN∆7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMN∆7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMN∆7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN.
These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMN∆7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.