Identification of Novel Biomarkers of Spinal Muscular Atrophy and Therapeutic Response by Proteomic and Metabolomic Profiling of Human Biological Fluid Samples

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations or deletions in SMN1 that lead to progressive death of alpha motor neurons, ultimately leading to severe muscle weakness and atrophy, as well as premature death in the absence of treatment. Recent approval of SMN-increasing medications as SMA therapy has altered the natural course of the disease. Thus, accurate biomarkers are needed to predict SMA severity, prognosis, drug response, and overall treatment efficacy. This article reviews novel non-targeted omics strategies that could become useful clinical tools for patients with SMA. Proteomics and metabolomics can provide insights into molecular events underlying disease progression and treatment response. High-throughput omics data have shown that untreated SMA patients have different profiles than controls. In addition, patients who clinically improved after treatment have a different profile than those who did not. These results provide a glimpse on potential markers that could assist in identifying therapy responders, in tracing the course of the disease, and in predicting its outcome. These studies have been restricted by the limited number of patients, but the approaches are feasible and can unravel severity-specific neuro-proteomic and metabolic SMA signatures.

Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study

“…Available clinical and omics studies on SMA population are mostly targeted approaches, and only a few non-targeted proteomic studies have been published so far [ 38 ]. In addition, the studies exploring metabolomic readouts [ 43 , 44 ] were performed with NMR, which provides reduced sensitivity in the identification of metabolites present at nM concentrations.…”

“…Four reports of untargeted proteomic analysis of blood and CSF from SMA patients are available, and we thoroughly reviewed them in [ 38 ]. Finkel et al performed a cross-sectional study on blood samples from a cohort of 108 SMA patients and reported a total of 200 candidate biomarkers that correlated with clinical scores [ 39 ].…”

Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy

“…Proteomic changes following nusinersen treatment have been studied by others [58]. A recent study using exploratory proteomic analysis in SMA type 1 patients showed that cathepsin D (CTSD), a lysosomal aspartyl protease, was down-regulated following nusinersen treatment, a change that was statistically significant only in responders in a larger sample [26].…”

“…Compared to previous studies, our study used a larger sample of 49 patients, spanning a heterogeneous range of ages, SMA types, and functional levels as seen in clinical practice. In addition, we used an exploratory approach by analyzing 1113 proteins through Olink's proximity extension assay to identify unsuspected therapeutic pathways and novel proteins that could predict motor improvement after nusinersen; only a few other studies have taken such a wide exploratory approach [26,27,58,61]. It is interesting that, except NEFL, none of the previously reported potential biomarkers of treatment response were identified within the four top proteins most predictive of motor improvement in our sample.…”

Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III

“…The diagnostic classification of SMA relies on its clinical presentation, which is often delayed and cannot be relied upon for making timely assessments. Therefore, accurate biomarkers are required for the prediction of SMA type, prognosis, drug response, and overall treatment effects 18 . Previous studies have performed metabolites on CSF from adult patients with SMA III and observed a correlation with CSF metabolites 19 .…”