MicroRNA Profiling May Provide Biomarkers for Monitoring MS

Caroline Helwick

October 16, 2013

NEW ORLEANS — Circulating microRNAs could be a readily accessible blood biomarker for diagnosing multiple sclerosis (MS) and monitoring disease activity, new research suggests.

"We found that circulating miRNAs are differentially expressed in relapsing-remitting MS, secondary progressive MS, and healthy control subjects," explained Howard Weiner, MD, codirector of the Center for Neurologic Diseases and director and founder of the Partners Multiple Sclerosis Center at Brigham and Women's Hospital, and Robert L. Kroc professor of neurology at the Harvard Medical School in Boston, Massachusetts.

The identification of immune biomarkers will allow a better understanding of an individual patient with MS, including response to therapy and disease stage, and progressive forms of MS, he explained.

Dr. Weiner discussed the topic during his Soriano Lectureship here at the American Neurological Association (ANA) 2013 Annual Meeting.

Studies Explore MicroRNAs as Biomarkers

MicroRNAs — single-stranded, small noncoding RNA molecules that regulate gene expression and protein synthesis — are involved in fundamental biologic processes. Dysregulated expression of microRNAs is associated with pathologic processes, including viral infections, cancer, and immune-related disorders.

"Thus, microRNAs provide a new avenue through which to understand immune regulation in a disease such as MS," Dr. Weiner noted. Because these molecules are stable in plasma and serum, they could be ideal immune biomarkers, he said.

Dr. Weiner and his colleagues have initiated several studies to determine whether microRNAs can be measured in plasma or serum and whether they can be used to distinguish relapsing-remitting from progressive forms of MS.

The ongoing CLIMB (Comprehensive Longitudinal Investigation of MS at Brigham and Women's Hospital) study seeks to better describe disease progression in treated patients and to identify predictors of progression using a combination of clinical and biologic measurements. CLIMB is evaluating the value of antigen arrays and microRNA profiling in more than 2200 patients.

The ongoing SUMMIT (Serial Unified Multicenter MS Investigation) study, being conducted by the International MS Consortium, seeks to identify risk factors and biomarkers of disease progression in 1500 patients and is evaluating serum antibody and microRNA signatures in a "working database of patients," Dr. Weiner said.

Differentiating MS Types

Data are already emerging that support the presence of different microRNAs and different antibody patterns of reactivity in the major MS types, he reported.

"Unique antibody patterns have been linked to different aspects of MS by MRI," he said. "One antibody pattern is linked to atrophy, whereas another pattern is linked to T2 lesions. Specific antibody patterns are associated with brain involvement, whereas others indicate spinal cord involvement. Furthermore, antilipid antibodies have demonstrated a close association with gray matter atrophy, suggesting that the modulation of lipid production by astrocytes could be a therapeutic target, he noted.

The differential expression of circulating microRNAs, which have been described in detail, has been linked to specific forms of MS and to treatment response or nonresponse, he said.

Dr. Weiner's team measured 368 microRNAs in 29 people with relapsing-remitting (RR) MS, secondary progressive (SP) MS, or no MS (healthy controls). They ultimately selected 19 microRNA candidates as predictors, which were validated in an independent dataset of 133 individuals.

"We can detect microRNAs in plasma, and the assay has minimum interassay variability," he said.

In addition to the different microRNA expression in the 3 groups, the team found that microRNA expression is linked to Expanded Disability Status Scale (EDSS) scores.

One example is the let-7 microRNAs, which regulate stem cell differentiation and T-cell activation, activate toll-like receptor-7, and are linked to neurodegeneration. The expression of the hsa-let-7 family of microRNAs can distinguish SPMS from healthy controls and can distinguish patients with RRMS from those with SPMS, Dr. Weiner noted.

Another example is the miR-92a-1 microRNAs, which have target genes involved in cell-cycle regulation and cell signaling. The expression of hsa-miR-92a-1, identified in the largest number of comparisons, can distinguish patients with RRMS from those with SPMS and healthy controls and is associated with EDSS score and disease duration.

On multivariate logistic regression for let-7a microRNA expression, the odds ratio for SPMS, compared with controls, was 0.34 (P = .001). For miR-92a-1 expression, the odds ratio for RRMS, compared with SPMS, was 1.35 (P = .022). For miR-30c expression, the odds ratio for RRMS, compared with controls, was 3.98 (P = .022).

Interestingly, circulating let-7 and miR-92 microRNAs, which were differentially expressed in RRMS and SPMS, were also differentially expressed in RRMS and amyotrophic lateral sclerosis (ALS). However, there was no difference in the expression of these microRNAs in SPMS and ALS, suggesting that similar processes occur in SPMS and ALS, he said.

In the future, researchers hope to validate the microRNA array results using polymerase chain reaction in the SUMMIT study population, to determine the biologic function and immune targets of differentially expressed microRNAs, and to test whether MS treatments can alter the expression of selected microRNAs.

"Disease progression, which is a heterogeneous process, is the next major therapeutic challenge in MS," Dr. Weiner added.

Need for Biomarkers in MS

"Diagnosing progressive MS can be clinically challenging," noted session moderator Robert Naismith, MD, assistant professor of neurology at the Washington University School of Medicine in St. Louis, Missouri.

"Patients can have a bad few months and then plateau for years. Do they have progressive MS? The studies described by Dr. Weiner can help us not only select the right treatment for patients and to discuss disease with patients, but to enroll patients in clinical trials," he told Medscape Medical News.

The field is moving forward at a fast pace, but work still must be done to establish the sensitivity and specificity of these assays for the individual patient, he explained. "The leap is how to apply these profiles to the individual," he added.

Dr. Weiner reports receiving personal compensation for activities with Biogen Idec, Novartis, and Serono. Dr. Naismith has disclosed no relevant financial relationships.

American Neurological Association (ANA) 2013 Annual Meeting. Presented October 13, 2013.

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