Open AccessElectrophysiological biomarkers in spinal muscular atrophy: proof of concept
Author(s) -
David Arnold W.,
Porensky Paul N.,
McGovern Vicki L.,
Iyer Chitra C.,
Duque Sandra,
Li Xiaobai,
Meyer Kathrin,
Schmelzer Leah,
Kaspar Brian K.,
Kolb Stephen J.,
Kissel John T.,
Burghes Arthur H. M.
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.23
Subject(s) - spinal muscular atrophy , sma* , medicine , compound muscle action potential , motor neuron , motor unit , electrophysiology , electromyography , pathology , neuroscience , disease , biology , anatomy , physical medicine and rehabilitation , mathematics , combinatorics
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 SMN ∆7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons ( ChAT Cre ). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMN ∆7 mice treated with antisense oligonucleotide ( ASO ) or gene therapy. Results 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 ChAT Cre 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 . Interpretation 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.