Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy

Abstract

Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.

New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

“…This knowledge would help to identify prognostic factors, to avoid long-term exposure to expensive drugs with still unknown long-term drug-related adverse events. A variety of biomarkers is currently under investigation including epigenetic, genetic, proteomic, electrophysiological and imaging tools [ 83 ]. Neurofilaments (NFs) muscle-specific miRNAs (myomiRs) and CSF proteomic profile, although biomarkers are not yet validated, have recently drawn attention as promising tools in SMA.…”

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

“…The considerable heterogeneity and slow disease progression in adults with SMA has contributed to the paucity of research and lack of efficacy in the limited number of trials to date. Clinical trials which could address this issue require long durations and robust clinical outcome measures, drawing attention to the need for biomarkers which are sensitive to changes in disease progression and/or response to disease modifying agents [120]. Unlike studies in infants and children with SMA, in which circulating neurofilaments are emerging as potential measures to assess disease progression and response to nusinersen treatment [121], no studies in adults with SMA have yielded a robust, reliable measurement [86,88,[122][123][124][125][126].…”

Advances in Treatment of Spinal Muscular Atrophy – New Phenotypes, New Challenges, New Implications for Care

“…Apart from SMN2 copy numbers, a variety of other possible biomarkers are currently discussed and investigated [62]. Within the ENDEAR study population, symptomatic SMA type 1 patients showed higher levels of plasma phosphorylated neurofilament heavy chain (pNF-H) than healthy controls.…”