Electrophysiological biomarkers in spinal muscular atrophy: proof of concept

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 Delta 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 Delta 7 mice treated with antisense oligonucleotide (ASO) or gene therapy. Results: CMAP was significantly reduced in SMN Delta 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 Delta 7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChAT(Cre) mice. MUNE in ASO-treated SMN Delta 7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMN Delta 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 Delta 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.