SMN mRNA and protein levels in peripheral blood: biomarkers for SMA clinical trials.
BACKGROUND
Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.


OBJECTIVE
To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.


METHODS
SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.


RESULTS
Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.


CONCLUSIONS
SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.
Sumner
C J
CJ
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA. sumnerc@ninds.nih.gov
Kolb
S J
SJ
Harmison
G G
GG
Jeffries
N O
NO
Schadt
K
K
Finkel
R S
RS
Dreyfuss
G
G
Fischbeck
K H
KH
D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D002986:Clinical Trials as Topic; D017362:Cyclic AMP Response Element-Binding Protein / Q000097:blood / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D007223:Infant; D008214:Lymphocytes; D009134:Muscular Atrophy, Spinal / Q000097:blood / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000097:blood / Q000235:genetics*; D012016:Reference Values; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein