Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

Abstract

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: The Working 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. The Working Group has identified needed information to continue efforts toward the validation of NF as a biomarker for SMA.

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia

“…However, plasma pNF-H levels show limited utility in detecting motor neuron degeneration, assessing its suppression, and reflecting therapeutic effects, particularly in individuals with SMA type 3 and a chronic disease phenotype. These findings underscore the need for further investigation of the applicability of pNF-H as a standalone candidate biomarker ( 21 ), including SMA individuals undergoing alternative SMN-dependent therapies, particularly within chronic SMA subgroups. Considering the rarity of the disease, the high cost of available therapies, as well as the projected decrease in symptomatic SMA cases in the future, a multicenter approach is recommended.…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…The debate is still ongoing regarding whether molecular biomarkers should be prioritized between imaging and electrophysiological biomarkers when monitoring disease progression and therapeutic response (since genetic biomarkers cannot be used to monitor therapeutic response). With the main purpose of addressing these issues, the recently formed SMA Multidisciplinary Biomarkers Working Group consists of 11 experts in the field of SMA research [106]. The main goal of this Working Group is to provide recommendations for the usage of prognostic, predictive, and pharmacodynamic biomarkers of SMA in clinical practice [106].…”

“…With the main purpose of addressing these issues, the recently formed SMA Multidisciplinary Biomarkers Working Group consists of 11 experts in the field of SMA research [106]. The main goal of this Working Group is to provide recommendations for the usage of prognostic, predictive, and pharmacodynamic biomarkers of SMA in clinical practice [106]. Several biomarkers have been considered: (1) biomolecular biomarkers (Nf, SMN protein, and muscle indicators [creatinine, creatine kinase, and markers of muscle damage]); (2) genetic biomarkers (copy number or polymorphisms of the SMN2 gene and the expression of modifier genes); (3) gene transcription and splicing regulators (miRNAs, long non-coding RNAs, methylation factors); (4) imaging biomarkers (EIM and muscle imaging using MRI); and (5) electrophysiological biomarkers (repetitive nerve stimulation (RNS), CMAP, and MUNE).…”

“…Several biomarkers have been considered: (1) biomolecular biomarkers (Nf, SMN protein, and muscle indicators [creatinine, creatine kinase, and markers of muscle damage]); (2) genetic biomarkers (copy number or polymorphisms of the SMN2 gene and the expression of modifier genes); (3) gene transcription and splicing regulators (miRNAs, long non-coding RNAs, methylation factors); (4) imaging biomarkers (EIM and muscle imaging using MRI); and (5) electrophysiological biomarkers (repetitive nerve stimulation (RNS), CMAP, and MUNE). The top biomarker among the aforementioned biomarkers was Nf, and the Working Group recommended Nf for further research and development since it showed prognostic, predictive, and pharmacodynamic potential [106].…”

“…Studies like the one performed by Glascock et al [106] are very important given the approval of three disease-modifying therapies for SMA and an increase in newborn screening for SMA.…”