Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study

Thomas Owen Crawford, Sergey V. Paushkin, Dione T. Kobayashi, Suzanne J. Forrest, Cynthia L. Joyce, Richard S. Finkel, Petra Kaufmann, Kathryn J. Swoboda, Danilo Tiziano, Rosa Lomastro, Rebecca H. Li, Felicia L. Trachtenberg, Thomas Plasterer, Karen S. Chen

Research output: Contribution to journalArticle

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. Conclusion: 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. Trial Registry: Clinicaltrials.gov NCT00756821.

Original languageEnglish (US)
Article numbere33572
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 27 2012

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Spinal Muscular Atrophy
muscular atrophy
Biomarkers
clinical trials
biomarkers
Proteins
proteins
Blood
Genes
Survival of Motor Neuron 1 Protein
Clinical Trials
Clinical Studies
blood
Tissue
prospective studies
Registries
phenotypic variation
Motivation
Healthy Volunteers
Prospective Studies

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. / Crawford, Thomas Owen; Paushkin, Sergey V.; Kobayashi, Dione T.; Forrest, Suzanne J.; Joyce, Cynthia L.; Finkel, Richard S.; Kaufmann, Petra; Swoboda, Kathryn J.; Tiziano, Danilo; Lomastro, Rosa; Li, Rebecca H.; Trachtenberg, Felicia L.; Plasterer, Thomas; Chen, Karen S.

In: PLoS One, Vol. 7, No. 4, e33572, 27.04.2012.

Research output: Contribution to journalArticle

Crawford, TO, Paushkin, SV, Kobayashi, DT, Forrest, SJ, Joyce, CL, Finkel, RS, Kaufmann, P, Swoboda, KJ, Tiziano, D, Lomastro, R, Li, RH, Trachtenberg, FL, Plasterer, T & Chen, KS 2012, 'Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study', PLoS One, vol. 7, no. 4, e33572. https://doi.org/10.1371/journal.pone.0033572
Crawford, Thomas Owen ; Paushkin, Sergey V. ; Kobayashi, Dione T. ; Forrest, Suzanne J. ; Joyce, Cynthia L. ; Finkel, Richard S. ; Kaufmann, Petra ; Swoboda, Kathryn J. ; Tiziano, Danilo ; Lomastro, Rosa ; Li, Rebecca H. ; Trachtenberg, Felicia L. ; Plasterer, Thomas ; Chen, Karen S. / Evaluation of SMN protein, transcript, and copy number in the biomarkers for spinal muscular atrophy (BforSMA) clinical study. In: PLoS One. 2012 ; Vol. 7, No. 4.
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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. Conclusion: 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. Trial Registry: Clinicaltrials.gov NCT00756821.",
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AU - Crawford, Thomas Owen

AU - Paushkin, Sergey V.

AU - Kobayashi, Dione T.

AU - Forrest, Suzanne J.

AU - Joyce, Cynthia L.

AU - Finkel, Richard S.

AU - Kaufmann, Petra

AU - Swoboda, Kathryn J.

AU - Tiziano, Danilo

AU - Lomastro, Rosa

AU - Li, Rebecca H.

AU - Trachtenberg, Felicia L.

AU - Plasterer, Thomas

AU - Chen, Karen S.

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