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SMN mRNA and protein levels in peripheral blood

Biomarkers for SMA clinical trials

From Neurogenetics Branch (C.J.S., G.G.H., K.H.F.) and Office of the Clinical Director (N.O.J.), National Institute of Neurological Disorders and Stroke, Bethesda, MD; Howard Hughes Medical Institute (S.J.K., G.D.), Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia; and Departments of Neurology and Pediatrics (K.S., R.S.F.), The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia.

Address correspondence and reprint requests to Dr. Charlotte J. Sumner, Neurogenetics Branch, NINDS, Bldg 35/Rm 2A1010, 35 Convent Drive, Bethesda, MD 20892; e-mail: sumnerc{at}ninds.nih.gov

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.

Conclusion: 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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 11 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on February 15, 2006, at www.neurology.org.

*The first two authors contributed equally to this study.

C.J.S. is supported by a National Institute of Neurologic Disorders and Stroke Career Transition Award (K22-NS0048199-01) and is the recipient of a Spinal Muscular Atrophy Foundation award. S.J.K. is supported by the MDA (MDA3867). C.J.S., G.G.H., and K.H.F. are supported by the Intramural Research Program of the NIH. G.D. is an Investigator of the Howard Hughes Medical Institute and is supported by funds from the Association Francaise Contre les Myopathies.

Disclosure: The authors report no conflicts of interest.

Received September 9, 2005. Accepted in final form December 16, 2005.

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