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. 2015 Nov 21:15:240.
doi: 10.1186/s12883-015-0495-x.

Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Michael Gurevich  1 , Gadi Miron  2 , Rina Zilkha Falb  3 , David Magalashvili  4 , Mark Dolev  5 , Yael Stern  6 , Anat Achiron  7   8
Affiliations

Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Michael Gurevich et al. BMC Neurol. .

Abstract

Background: Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment.

Methods: SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR.

Results: One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60% of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate.

Conclusion: Within the IFN treated SPMS population, 60% of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment.

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Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Differential gene expression of RRMS IFN responders compared to untreated RRMS. a. Volcano plot - Each dot represents a gene, red dots demonstrate positive fold change and blue negative fold change. Cut off line showing p-value level of 0.05 by Bonferroni multiple correction, with 104 DEG’s above cut off line. b. Enrichment of IFN signaling pathway within RRMS IFN responders. Up-regulated genes are marked in red
Fig. 3
Fig. 3
Clustering of SPMS patients based on 104 DEGs. Heatmap depicting hierarchical clustering of SPMS patients according to expression of 104 DEGs, upregulated genes demonstrated in red and down regulated in blue. The left vertical panel presents treatment status of SPMS patients: non treated -purple, IFN treated transcriptional responders- green, IFN treated transcriptional non-responders - yellow
Fig. 4
Fig. 4
qRT-PCR verification of key IFN inducible genes. Expression of IFN induced (a) IFI44 and (b) OAS1 in SPMS IFN treated patients
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