A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein

Noriko Otsuki; Reiko Arakawa; Kaori Kaneko; Ryoko Aoki; Masayuki Arakawa; Kayoko Saito

doi:10.1371/journal.pone.0201764

A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein

PLoS One. 2018 Aug 13;13(8):e0201764. doi: 10.1371/journal.pone.0201764. eCollection 2018.

Authors

Noriko Otsuki¹, Reiko Arakawa¹, Kaori Kaneko², Ryoko Aoki¹, Masayuki Arakawa³, Kayoko Saito^{1

2}

Affiliations

¹ Institute of Medical Genetics, Tokyo Women's Medical University, 10-22 Kawadacho, Shinjuku-ku, Tokyo 162-0054, Japan.
² Affiliated Field of Medical Genetics, Division of Biomedical Engineering and Science, Graduate Course of Medicine, Graduate School of Tokyo Women's Medical University, 10-22 Kawadacho, Shinjuku-ku, Tokyo 162-0054, Japan.
³ Laboratory of Virology, Institute of Microbial Chemistry, 5-14-23 Kamiosaki, Shinagawa-ku Tokyo 141-0021, Japan.

Abstract

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by insufficiency of functional survival motor neuron (SMN) protein. Several clinical trials have been conducted with the aim of upregulating the expression of the SMN protein in SMA patients. In order to evaluate the efficiency of these SMN-targeted approaches, it has become necessary to verify SMN protein levels in the cells of SMA patients. Accordingly, we have developed a method allowing the evaluation of the functional SMN protein with < 1.5 mL of peripheral blood using imaging flow cytometry. The expression of SMN protein in CD3+, CD19+, and CD33++ cells obtained from SMA patients, was significantly reduced compared with that in cells from control subjects. In spot analysis of CD33++ cells, the intensities of SMN spots were significantly reduced in SMA subjects, when compared with that in controls. Therefore, SMN spots implied the presence of functional SMN protein in the cell nucleus. To our knowledge, our results are the first to demonstrate the presence of functional SMN protein in freshly isolated peripheral blood cells. We anticipate that SMN spot analysis will become the primary endpoint assay for the evaluation and monitoring of therapeutic intervention, with SMN serving as a reliable biomarker of therapeutic efficacy in SMA patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Antigens, CD19 / blood
Biomarkers / blood
CD3 Complex / blood
Child
Child, Preschool
Female
Humans
Infant
Male
Middle Aged
Muscular Atrophy, Spinal / blood*
Sialic Acid Binding Ig-like Lectin 3 / blood
Survival of Motor Neuron 1 Protein / blood*
Survival of Motor Neuron 2 Protein / blood
Young Adult

Substances

Antigens, CD19
Biomarkers
CD19 molecule, human
CD3 Complex
CD33 protein, human
SMN1 protein, human
SMN2 protein, human
Sialic Acid Binding Ig-like Lectin 3
Survival of Motor Neuron 1 Protein
Survival of Motor Neuron 2 Protein

Grants and funding

This work was supported by The Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development, AMED (URL: https://www.amed.go.jp/), Grant number: 16ek0109086h0002, Principal Investigator: Dr. Kayoko Saito; The Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan (URL: http://plaza.umin.ac.jp/neuro2/), Grant number: H29-nannchitou(nann)-ippann-033, Investigator: Dr. Kayoko Saito; Japan Society for the Promotion of Science, JSPS Grants-in-Aid for Scientific Research (URL: https://www.jsps.go.jp/j-grantsinaid/), Grant number: 26860829, Principal Investigator: Dr. Reiko Arakawa; and Japan Society for the Promotion of Science, JSPS Grants-in-Aid for Scientific Research (URL: https://www.jsps.go.jp/j-grantsinaid/), Grant number: 26461555, Principal Investigator: Dr. Masayuki Arakawa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.