Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

Background: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients. Validation of a reliable biomarker(s) with the potential to support early diagnosis, inform disease prognosis and therapeutic suitability, and/or confirm response to treatment(s) represents a significant unmet need in SMA. Objectives: The SMA Multidisciplinary Biomarkers Working Group, comprising 11 experts in a variety of relevant fields, sought to determine the most promising candidate biomarker currently available, determine key knowledge gaps, and recommend next steps toward validating that biomarker for SMA. Methods: The Working Group engaged in a modified Delphi process to answer questions about candidate SMA biomarkers. Members participated in six rounds of reiterative surveys that were designed to build upon previous discussions. Results: TheWorking Group reached a consensus that neurofilament (NF) is the candidate biomarker best poised for further development. Several important knowledge gaps were identified, and the next steps toward filling these gaps were proposed. Conclusions: NF is a promising SMA biomarker with the potential for prognostic, predictive, and pharmacodynamic capabilities. TheWorking Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.