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Published on: June 14, 2018
Dynamics of interferon-beta modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-beta
Roseane Santos1, Bianca Weinstock-Guttman, Miriam Tamaño-Blanco
1Department of Pharmaceutical Sciences, State University of New York at Buffalo, and Jacobs Neurological Institute, Buffalo General Hospital, NY 14260-1200, United States.
Abstract:
The objective of this study was to evaluate multiple interferon (IFN) specific mRNA biomarkers in multiple sclerosis (MS) patients with anti-IFN-beta neutralizing antibodies (NAB) using a pharmacodynamic study design. Thirty patients were enrolled. Blood samples were drawn at pre-treatment, 4-, 8-h time points following the intramuscular dose of IFN-beta-1a. Total RNA was obtained from peripheral blood cells, processed to cDNA and analyzed using quantitative real-time polymerase chain reaction. Pre-treatment serum samples were analyzed for anti-IFN-beta binding and neutralizing antibodies: 22 patients were NAB negative; equal numbers of the eight remaining patients were either NAB positive or had borderline NAB status. The results showed that early assessment (at 4 h after IFN-beta injection) of mRNAs for Stat-1, MxA, MxB and TRAIL was more sensitive than the later measurements. Furthermore, the NAB positive patients had strongly attenuated gene expression responses on all the mRNAs. Patients with borderline NAB had average responses that appear to be lower than NAB negative patients on several genes, notably Stat-1, TRAIL and beta2 microglobulin.
Insights
Neutralizing antibodies (NAB) against interferon-beta (IFN-beta) in multiple sclerosis (MS) patients significantly reduce the gene expression response to IFN-beta therapy. Early mRNA biomarker assessment is more sensitive for evaluating treatment effects.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
- Interferon-beta (IFN-beta) is a common treatment for MS, but its efficacy can be limited by the development of neutralizing antibodies (NAB).
- Understanding the impact of NAB on IFN-beta pharmacodynamics is crucial for optimizing treatment strategies.
Purpose of the Study:
- To evaluate specific interferon (IFN) mRNA biomarkers in multiple sclerosis (MS) patients treated with IFN-beta-1a.
- To assess the influence of anti-IFN-beta neutralizing antibodies (NAB) on gene expression responses.
- To determine the optimal time point for measuring pharmacodynamic changes.
Main Methods:
- A pharmacodynamic study design was employed with 30 MS patients receiving intramuscular IFN-beta-1a.
- Blood samples were collected at pre-treatment, 4-h, and 8-h post-injection.
- Quantitative real-time polymerase chain reaction (qPCR) analyzed mRNA levels of Stat-1, MxA, MxB, and TRAIL.
- Anti-IFN-beta binding and neutralizing antibodies were measured in serum.
Main Results:
- Early assessment (4 hours post-injection) of Stat-1, MxA, MxB, and TRAIL mRNA showed higher sensitivity.
- Patients positive for NAB exhibited significantly attenuated gene expression responses.
- Borderline NAB status was associated with reduced responses in genes like Stat-1 and TRAIL compared to NAB-negative patients.
Conclusions:
- Neutralizing antibodies (NAB) strongly impair the pharmacodynamic response to interferon-beta (IFN-beta) in multiple sclerosis (MS) patients.
- Early measurement of specific mRNA biomarkers (Stat-1, MxA, MxB, TRAIL) is effective for assessing IFN-beta treatment effects.
- NAB status is a critical factor influencing treatment efficacy and should be monitored.
