Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

Abstract

BackgroundSpinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets.Objective:To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches.Materials and Methods:A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2–12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures.ResultsA total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS.DiscussionIn this cross-sectional study, “BforSMA” (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm these findings, demonstrate sensitivity to change with disease progression, and assess potential impact on clinical trial design.Trial Registry Clinicaltrials.gov NCT00756821.

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

“…Very recently, some of us (FDT and LR) have collaborated to the BforSMA study. 39,40 Also in that large cohort of young patients spanning the whole phenotypic spectrum of the disease, SMN2-fl levels were significantly higher in the less severely affected subjects, although they were not predictive of the motor performance of single individuals. We found similar results also in our previous study.…”

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

“…Frozen samples were sent to a central processing laboratory at Myriad and processed to quantify 25 plasma protein analytes that have been identified as putative serum SMA biomarkers 31, 32. All samples were stored at −80°C until tested.…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…Development of non-SMN molecular biomarkers using proteomic, metabolomics, and transcriptomic approaches holds promise for SMA, even though these measures may not be able to distinguish primary (initiating) and secondary (responsive) changes in gene expression. The recent BforSMA study identified a new set of 27 validated plasma protein SMA biomarkers significantly associated with motor function and other measures of SMA disease activity, and a commercial SMA-MAP biomarker panel was generated [128,129]. Further studies will be required to investigate sensitivity to change with disease progression, and assess potential impact on clinical trial design.…”