Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

Abstract

BackgroundThe universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early “biomarker” of treatment effect.MethodsA cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age.ResultsSMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other.ConclusionThis is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an “early look” for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number.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.…”

Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy

“…Correlation analysis revealed that there was no association between SMN2 CGIs methylation levels and total SMN2 transcript levels (SMN2-fl+SMN2-7) (Crawford et al, 2012). However, 3/8 differentially methylated CpG units correlated with different SMN2 transcripts after applying a Bonferroni correction (P<0.017).…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…Aligned with therapeutic approaches designed to increase SMN levels, efforts to develop candidate biomarkers have also concentrated on measurement of SMN protein expression. While this can reliably be measured in peripheral blood and relates to SMA type, SMN protein levels do not predict severity of motor function, and it remains to be determined if this reflects what is happening in motor systems [126,127]. 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.…”