Update on Biomarkers in Spinal Muscular Atrophy

Abstract

The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. SMN2 copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. Recent therapeutic advancements in SMA have shown promising results, though there is still a great need to identify and understand the impact of biomarkers in modulating disease onset and progression.

Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Display Altered Proteomes at Early Stages of Differentiation

“…Also, efforts have been made to identify biomarkers for SMA, such as SMN mRNA and protein levels, neurofilament proteins plasma protein analytes, creatine kinase, creatinine, and various electrophysiology and imaging measures. 29 Discovery of new biomarkers that are linked to SMA disease processes will be of interest for future studies involving longitudinal follow-up of patients, for example, during treatment. Here, we describe the use of human iPSC technology and mass spectrometry to quantitatively study proteome changes during the entire timeline of MN differentiation in SMA patients and control cells.…”

“…Improved insights into the mechanisms that underlie SMA are important because they may inform treatment strategies (e.g., to delineate the therapeutic window of opportunity in patients) and result in the identification of new therapeutic targets. Also, efforts have been made to identify biomarkers for SMA, such as SMN mRNA and protein levels, neurofilament proteins plasma protein analytes, creatine kinase, creatinine, and various electrophysiology and imaging measures . Discovery of new biomarkers that are linked to SMA disease processes will be of interest for future studies involving longitudinal follow-up of patients, for example, during treatment.…”

“… 28 Efforts have been made to identify biomarkers for SMA, which resulted in a number of molecular biomarkers such as the SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins’ plasma protein analytes, creatine kinase, creatinine, and various electrophysiology and imaging measures. 29 The study of early neurodevelopmental processes in disorders such as SMA has become feasible through the generation of induced pluripotent stem cells (iPSCs), derived from, for example, human fibroblasts, which hold great promise in the investigation of neurological diseases. 30 This technology has made it possible to generate human neurons, including MNs, to study disease mechanisms and potentially identify (better) treatments for human disorders.…”

“…Furthermore, SMA is often studied at late stages in pathogenesis, but it is becoming increasingly apparent that abnormal (neuro) development is a critical component of SMA pathology and that early therapeutic intervention will be necessary . Efforts have been made to identify biomarkers for SMA, which resulted in a number of molecular biomarkers such as the SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins’ plasma protein analytes, creatine kinase, creatinine, and various electrophysiology and imaging measures . The study of early neurodevelopmental processes in disorders such as SMA has become feasible through the generation of induced pluripotent stem cells (iPSCs), derived from, for example, human fibroblasts, which hold great promise in the investigation of neurological diseases .…”

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy

“…However, we have a limited understanding of the biochemical abnormalities associated with SMA pathology and the metabolic effects of SMN-inducing therapies in the CNS of patients. Moreover, despite increasing efforts to identify the biomarkers of disease progression and therapeutic efficacy [ 25 , 26 , 27 , 28 , 29 , 30 ], there has been a paucity of metabolomic studies focused on the cerebrospinal fluid (CSF) of SMA patients [ 31 ], which would have the unique potential to provide direct insights into the disease-associated neurochemical disturbances as well as the therapy-induced changes of CNS-related metabolism, both of which are unknown.…”