title: Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  SMN2 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.
  
  
  CONCLUSIONS
  This 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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00756821.
authors.affiliation: Departments of Neurology and Pediatrics, The Johns Hopkins University, Baltimore, Maryland, United States of America. tcrawfo@jhmi.edu
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Paushkin
authors.forename: Dione T
authors.initials: DT
authors.lastname: Kobayashi
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Forrest
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Joyce
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.forename: Petra
authors.initials: P
authors.lastname: Kaufmann
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Danilo
authors.initials: D
authors.lastname: Tiziano
authors.forename: Rosa
authors.initials: R
authors.lastname: Lomastro
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Li
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Plasterer
authors.forename: Karen S
authors.initials: KS
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D056915:DNA Copy Number Variations / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D055540:Survival of Motor Neuron 2 Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017931:DNA Primers; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein