Role of circulating biomarkers in spinal muscular atrophy: insights from a new treatment era

Spinal muscular atrophy (SMA) is a lower motor neuron disease due to biallelic mutations in the SMN1 gene on chromosome 5. It is characterized by progressive muscle weakness of limbs, bulbar and respiratory muscles. The disease is usually classified in four different phenotypes (1-4) according to age at symptoms onset and maximal motor milestones achieved. Recently, three disease modifying treatments have received approval from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while several other innovative drugs are under study. New therapies have been game changing, improving survival and life quality for SMA patients. However, they have also intensified the need for accurate biomarkers to monitor disease progression and treatment efficacy. While clinical and neurophysiological biomarkers are well established and helpful in describing disease progression, there is a great need to develop more robust and sensitive circulating biomarkers, such as proteins, nucleic acids, and other small molecules. Used alone or in combination with clinical biomarkers, they will play a critical role in enhancing patients' stratification for clinical trials and access to approved treatments, as well as in tracking response to therapy, paving the way to the development of individualized therapeutic approaches. In this comprehensive review, we describe the foremost circulating biomarkers of current significance, analyzing existing literature on non-treated and treated patients with a special focus on neurofilaments and circulating miRNA, aiming to identify and examine their role in the follow-up of patients treated with innovative treatments, including gene therapy.