Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

被引：126

作者：

Crawford, Thomas O. ^{[1
,2
]}

Paushkin, Sergey V. ^{[3
]}

Kobayashi, Dione T. ^{[3
]}

Forrest, Suzanne J. ^{[3
]}

Joyce, Cynthia L. ^{[3
]}

Finkel, Richard S. ^{[4
,5
,6
]}

Kaufmann, Petra ^{[7
]}

Swoboda, Kathryn J. ^{[8
,9
]}

Tiziano, Danilo ^{[10
]}

Lomastro, Rosa ^{[10
]}

Li, Rebecca H. ^{[11
]}

Trachtenberg, Felicia L. ^{[11
]}

Plasterer, Thomas ^{[12
]}

Chen, Karen S. ^{[3
]}

机构：

[1] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA

[3] Spinal Muscular Atrophy Fdn, New York, NY USA

[4] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[6] Univ Penn, Sch Med, Philadelphia, PA 19104 USA

[7] Columbia Univ, Dept Neurol, New York, NY USA

[8] Univ Utah, Sch Med, Dept Neurol, Salt Lake City, UT USA

[9] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA

[10] Univ Cattolica S Cuore, Inst Med Genet, Rome, Italy

[11] New England Res Inst Inc, Watertown, MA USA

[12] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA

来源：

PLOS ONE | 2012年 / 7卷 / 04期

基金：

美国国家卫生研究院;

关键词：

SURVIVAL MOTOR-NEURON; PLACEBO-CONTROLLED TRIAL; CRITICAL EXON; MESSENGER-RNA; SPLICING SILENCER; PERIPHERAL-BLOOD; DOUBLE-BLIND; PHENOTYPE; ELEMENT; GENE;

D O I：

10.1371/journal.pone.0033572

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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