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
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that manifests across a wide range of severity
Planning and Objectives The protocol was developed by a combination of Spinal Muscular Atrophy (SMA) patient advocates, experts in biostatistics and bioinformatics, basic scientists investigating the biology of SMA, drug metabolism and pathway experts, and clinical trial specialists
Enrollment figures slightly exceeded the original targets for each group due to replacement, per protocol, of subjects in whom specimens were of insufficient quantity (n = 7) or quality (n = 3)
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that manifests across a wide range of severity. A wide range of disease severity can be partially attributed to the presence of variable copy number of a neighboring near-identical gene, SMN2 (Gene ID = 6607) [1,2,3]. The invariable presence of the partially functional diseaseameliorating SMN2 gene in individuals with SMA offers an attractive target for development of therapeutics [9]. Proof-ofconcept studies with small molecule, antisense oligonucleotide or gene therapy approaches targeting various mechanisms to upregulate expression of SMN2 have extended survival and improved motor function in SMN-deficient animal models [10,11,12,13,14,15,16]. The 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. 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
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