title: Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 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 SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy.
  
  
  RESULTS
  CMAP was significantly reduced in SMNΔ7 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 SMNΔ7 mice but not controls (p=0.02). Similar findings were seen at 21 days inChATCremice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN.
  
  
  CONCLUSIONS
  These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 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.
authors: Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12 Ave, Columbus, Ohio 43210 ; Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, 480 Medical Center Drive Columbus, Ohio 43210.
authors: W David
authors: WD
authors: Arnold
authors: Department of Neurosurgery, The Ohio State University Wexner Medical Center, 410 West 10th Avenue Columbus Ohio 43210.
authors: Paul N
authors: PN
authors: Porensky
authors: Department of Molecular & Cellular Biochemistry, Wexner Medical Center, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio 43210.
authors: Vicki L
authors: VL
authors: McGovern
authors: Department of Molecular & Cellular Biochemistry, Wexner Medical Center, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio 43210.
authors: Chitra C
authors: CC
authors: Iyer
authors: Department of Molecular & Cellular Biochemistry, Wexner Medical Center, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio 43210.
authors: Sandra
authors: S
authors: Duque
authors: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210.
authors: Xiaobai
authors: X
authors: Li
authors: Nationwide Children's Hospital Research Institute, Columbus, Ohio 43205.
authors: Kathrin
authors: K
authors: Meyer
authors: Nationwide Children's Hospital Research Institute, Columbus, Ohio 43205.
authors: Leah
authors: L
authors: Schmelzer
authors: Nationwide Children's Hospital Research Institute, Columbus, Ohio 43205 ; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210.
authors: Brian K
authors: BK
authors: Kaspar
authors: Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12 Ave, Columbus, Ohio 43210 ; Department of Molecular & Cellular Biochemistry, Wexner Medical Center, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio 43210.
authors: Stephen J
authors: SJ
authors: Kolb
authors: Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12 Ave, Columbus, Ohio 43210 ; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210.
authors: John T
authors: JT
authors: Kissel
authors: Department of Molecular & Cellular Biochemistry, Wexner Medical Center, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, Ohio 43210 ; Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12 Ave, Columbus, Ohio 43210.
authors: Arthur H M
authors: AH
authors: Burghes